Le programme pancanadien de recherche du RCS vise à soutenir la recherche translationnelle de classe mondiale en médecine régénératrice sur l’ensemble du continuum de la recherche afin de procurer des bienfaits sanitaires, sociaux et économiques aux Canadiens et aux Canadiennes.
Utilisez la base de données consultable ci-dessous pour en savoir plus sur les projets et les essais cliniques sur les cellules souches et la médecine régénératrice qui ont été financés par le RCS de 2016 à 2025.
*Remarque : les renseignements sur les subventions sont présentés dans la langue utilisée par les demandeurs, ce qui peut avoir une incidence sur les résultats des recherches faites dans la base de données.
Acronymes et abréviations :
(P) Chercheur principal d’un projet
(C) Cochercheur d’un projet
Base de données des recherches financées par le RCS
Année
Nom complet
Établissement
Programme
Nom du chercheur principal
Rôle du chercheur
Membres de l'équipe financés
Montant du financement
Titre du projet
Résumé du projet
Mots-clés fournis par les chercheurs
Project Abstract/ Summary
Date de début du projet
Date de fin du projet
Détails
2016
Sandra Cohen (P)
Hôpital Maisonneuve-Rosemont
Subventions de soutien des essais cliniques
Cohen
Chercheur principal
Sandra Cohen
999 968
Making cord blood hematopoietic stem cell expansion competitive
Sang
Allogeneic hematopoietic stem cell (HSC) transplant is the best available therapy to cure blood cancers. Unfortunately, 1/3 of patients do not have a matched donor (related or unrelated). Cord blood (CB) is an attractive alternative donor source due to its unique properties, including permissive mismatches, low incidence of chronic graft-versus-host disease (cGVHD) and rapid availability. A lower risk of cGVHD is very important as it is the major determinant of long-term quality of life after transplant. However, these advantages are offset by the limited cell dose (i.e. small cords), which results in delayed- or non-engraftment (recovery of blood counts), increased infections, prolonged hospitalization and early mortality. In February 2016 we launched a CB expansion clinical trial to translate to the clinic 2 Canadian discoveries, a compound developed in G. Sauvageau and A. Marinier’s laboratory (UM171) and a bioreactor system (fed-batch) from P. Zandstra’s laboratory. Combined together these ground-breaking technologies aim to increase the HSC content of CBs and reduce the associated complications.
Our long-term objective is to design newly engineered CB grafts which will combine rapid (<12 days) engraftment with maximal anti-tumor effect (cord blood T cells) and minimal side effects (low transplant related mortality and GVHD). To achieve this, we have brought together a Canadian multidisciplinary team with state-of-the-art expertise in stem cell biology, immunology, bioengineering, cell therapy and clinical transplantation.
We seek financial support to recruit additional patients to our ongoing trial to dramatically increase the competitiveness of our strategy. We will introduce 2 modifications in our manufacturing protocol, significantly reducing cost and increasing efficacy. Consequently, we will be able to initiate a minor modification in our transplantation procedure that will minimize the risk of acute GVHD, a complication that remains too frequent. In parallel, a socio-economical study will allow us to best position our expansion strategy within Canada and internationally.
Once completed, results from this trial will be transferred to our commercial vector ExCellThera, a recently created Canadian biotech. All these improvements should make expanded CB a very desirable product for patients as well as for society and could challenge the current gold standard of matched related and unrelated donor transplants. In 3-4 years we should be in a position to initiate a multicenter enlarged phase II trial to confirm efficacy and efficiency of our product, which could be paradigm changing in the field of HSC transplantation.
1 December 2016
31 December 2017
2016
Duncan Stewart (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien des essais cliniques
Stewart
Chercheur principal
Duncan Stewart
999 546
Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI)
Cardiaque
Rationale: Patients with a large area of damaged heart muscle after a heart attack have a high risk for heart failure and death. Cell-based gene therapy could restore working muscle in regions that otherwise would form only scar, and lead to better heart repair and function.
Purpose: The primary objectives of the ENACT-AMI trial are to determine whether the administration of a patient’s own (autologous) Endothelial Progenitor Cells (EPCs) is safe and effective in improving cardiac function following large heart attack, and whether the use of cells that are genetically engineered by adding extra copies of a gene that is critical for blood vessel function and repair, namely endothelial Nitric Oxide Synthase (eNOS), is superior to non-modified cells. A secondary objective is to determine whether the benefit of EPC therapy depends on the timing of cell delivery (5-15 days versus 16-30 days post-STEMI).
Novel aspects: The use of the patient’s own cells avoids the immunological rejection that occurs with transplantation of cells from other individuals, but is greatly hampered by the fact that the reparative activities of stem and progenitor cells are negatively influenced by the host risk factors that lead to heart disease in the first place, namely advanced age, high cholesterol, diabetes and so forth. We have shown that adding extra copies of the eNOS gene (which protects blood vessels and promotes their growth and repair) can restore the activity of EPCs from heart patients by almost 90%. ENACT-AMI is the first clinical trial in the world to include a strategy designed to enhance the function of a patient’s own cells, and the first to use combination gene and cell therapy, for the treatment of heart disease.
Benefits to Canadians and Canada: While outcomes after heart attacks have greatly improved with the advent of modern therapies to open up the blocked coronary artery (reperfusion therapy), about 20% of patients fail to receive the expected benefits of reperfusion therapy, and face the consequences of large heart damage and subsequent heart failure. Should gene-enhanced EPCs provide an effective adjunctive treatment for these patients, this would avoid a high individual burden of chronic debilitating disease, while reducing the high costs to the health care system which in Canada totals $2.8 billion per year for heart failure (heartandstroke.ca/heartreport). If successful, ENACT investigators are well positioned to disseminate such a therapy across Canada though CellCAN, a unique network of cell manufacturing facilities across Canada.
1 December 2016
31 December 2017
2016
Harold Atkins (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien des essais cliniques
Atkins
Chercheur principal
Harold Atkins
215 700
Using hematopoietic stem cell transplantation to regenerate a naïve immunie system tolerant to liver allografts
Insuffisance hépatique
Although short-term results for liver transplantation are excellent, the need for immunosuppression limits quality of life and long-term survival. Many transplant patients develop post-transplant complications including renal failure, cardiovascular disease, neoplasms, and life-threatening infections. The ability to induce a state of operational tolerance, that is, graft acceptance without the need for long-term immunosuppression, would be a major advance in the field, cutting the ongoing costs of immune suppression and reducing medical complications of organ transplantation and the associated costs to the health care system.
We propose an open-label, non-regulated, REB approved, proof-of-principle trial to determine whether immunological tolerance can be created following ablation of pre-existing allograft reactive immunity and regeneration of a naive immune system from an autologous hematopoietic stem cell transplant, in recipients of a liver allograft.
By 31-December-2017, we propose to complete the intervention on 10 patients. Safety data would be available on 9 patients and preliminary efficacy data on 7 patients. By the end of the following year, safety and 1 year efficacy data would be available on all 10 recipients. Correlative studies will examine the composition and functionality of the regenerated immune system, the nature of tolerance (or reactivity) to the liver allograft and whether a previously reported gene signature can predict tolerance to the liver graft.
Key team members include Dr. G Levy directing the liver transplant team at University Health Network and Dr. H Atkins directing the HSCT team at The Ottawa Hospital. Key partners include Novartis, which is supplying Everolimus, a regulatory T cell expanding agent, for the trial and the Birmingham Foundation, which is helping defray patient living expenses. A test for determining immunological tolerance is a potential commercial offshoot of this work.
Positive results, that is 50% or more of the patients are free from rejection without immune suppression, would provide sufficient evidence to confirm the results in a randomized Phase IIB trial and would support additional Phase IIA trials testing the ability of auHSCT to generate tolerant immune systems in other (kidney, heart…) allograft recipients. Future studies would also test the ability to regenerate self-tolerant immune systems for patients with autoimmune liver diseases – potentially preventing endstage organ damage and the need for liver transplantation.
1 December 2016
31 December 2017
2016
Lauralyn McIntyre (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien des essais cliniques
McIntyre
Chercheur principal
Lauralyn McIntyre
1 000 000
Cellular Immunotherapy for Septic Shock (CISS): A Phase II Multicentre Clinical Trial
Septicémie
Cellular Immunotherapy for Septic Shock (CISS): A Phase II Multicentre Clinical Trial
1 December 2016
31 December 2017
2016
James Shapiro (P)
University of Alberta
Subventions de soutien des essais cliniques
Shapiro
Chercheur principal
James Shapiro
499 596
Clinical trials in stem cell transplantation - solving the supply and the survival problem in Type 1 diabetes
Diabète
Diabetes is the 7th leading cause of death in North America, the leading cause of renal failure, non-traumatic limb amputations, and new cases of blindness in adults. Mortality rates of Canadians with diabetes are almost twice those without the disease. The burden to our healthcare system is staggering, with annual diabetes costs of $1.1 billion.
Presently there is no known cure. Considering the disadvantages of current available treatments, we propose the following two clinical trials (VC-01 and Autologous CD34+ Stem Cell Therapy trials) that we anticipate will contribute to more efficient and cost-effective novel treatments to T1DM and some T2DM:
• VC-01 Trial to treat patients with longstanding T1DM
The goal of this trial is to evaluate a potentially limitless source of human embryonic stem cell derived new β -cells, as a substitute for clinical islet transplantation from cadaveric donors, in a first-in human clinical study. ViaCyte Inc. has led the field with consistent progress in the development of a clinically applicable β -cell line. Ultimately, this cell source could be used to restore β -cell mass in patients with T1DM and T2DM.
Hypothesis:
Transplantation of PEC-01 stem cell derived β-cells will mature in patients with T1DM, secrete insulin in response to glucose, and be sufficiently potent to reduce or eliminate the need for exogenous insulin. When implanted within an immunoisolating device (Encaptra®), no immunosuppression will be required.
If successful, it would be perceived as a major step forward towards a durable T1DM cure.
• Autologous CD34+ Stem Cell Therapy Trial to restore self-tolerance and drive β -cell regeneration without need for immunosuppression in patients with new-onset T1DM.
The goal of this trial is to demonstrate that subjects with new-onset T1DM undergoing autologous hematopoetic stem cell mobilization and immunologic reset will have greater preservation of endogenous insulin secretion compared to controls, and foremost that the treatment is safe, without myeloablation or need for chronic immunosuppression
Hypothesis:
T-depletional and anti-inflammatory treatment will restore self-tolerance in T1DM and mobilization of autologous CD34+ stem cells coupled with a long-acting glucagon-like Peptide-1 (GLP-1) analogue, will promote pancreatic islet regeneration and repair in the absence of myeloablation.
There has been remarkable progress in understanding the potential role of sub-populations of bone marrow derived stem cells in facilitating tissue repair. Coupled with ‘immunologic reset’ to disrupt autoimmunity, this approach offers tremendous curative potential in T1DM. A large collaboration team has been established for these two trials.
1 December 2016
31 December 2017
2016
Timothy Kieffer (P)
University of British Columbia
Subventions de soutien des essais cliniques
Kieffer
Chercheur principal
Timothy Kieffer, Garth Warnock, Graydon Meneilly, Megan Levings, David Thompson, Bruce Verchere
35 431
A stem cell therapy for insulin replacement in patients with diabetes
Diabète
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921 and developed methods to purify it to provide a source for patients to inject. While life-sustaining, many patients with diabetes face a life-long routine of daily insulin injections and blood glucose measurements and suffer from several debilitating complications of the disease that severely reduce quality of life. Cell replacement therapy using islet cells obtained from organ donors has proven to be a highly effective treatment for diabetes. In fact, some islet recipients are completely insulin-independent five years after their transplant, and some even remain insulin-independent as long as ten years. However, use of this therapy is severely restricted due to a limited supply of donor organs and the high cost of the procedure. Stem cell-derived islet replacement can overcome both the supply and cost limitations of cadaveric islet replacement. The California company ViaCyte is developing a pancreatic progenitor product from human stem cells that represents a renewable, cost-effective source of cells for islet replacement. Moreover, ViaCyte has developed a device that can contain the cells and is designed for implant under the skin. Clinical testing of this potential product is now underway, and initial results with low doses of cells indicate the procedure is safe.
In this project the Vancouver team aims to recruit patients with type 1 diabetes to examine if higher doses of the cells can restore normal control of blood glucose levels and reduce, or even eliminate, the need for insulin injections. The team consists of surgeon Dr. Garth Warnock, the first to successfully transplant donor islets in patients in Canada, and co-developer of the so-called “Edmonton Protocol” for islet transplant, clinicians Dr. David Thompson and Dr. Graydon Meneilly who are experts in diabetes management and will carefully follow the patients enrolled in the trial, Dr. Megan Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, and project leader Dr. Timothy Kieffer, an authority on cell therapy for diabetes whose laboratory research on stem cells provides strong scientific support for the trial. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes, putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 December 2016
31 December 2017
2016
David Thompson (C)
University of British Columbia
Subventions de soutien des essais cliniques
Kieffer
Cochercheur
Timothy Kieffer, Garth Warnock, Graydon Meneilly, Megan Levings, David Thompson, Bruce Verchere
185 021
A stem cell therapy for insulin replacement in patients with diabetes
Diabète
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921 and developed methods to purify it to provide a source for patients to inject. While life-sustaining, many patients with diabetes face a life-long routine of daily insulin injections and blood glucose measurements and suffer from several debilitating complications of the disease that severely reduce quality of life. Cell replacement therapy using islet cells obtained from organ donors has proven to be a highly effective treatment for diabetes. In fact, some islet recipients are completely insulin-independent five years after their transplant, and some even remain insulin-independent as long as ten years. However, use of this therapy is severely restricted due to a limited supply of donor organs and the high cost of the procedure. Stem cell-derived islet replacement can overcome both the supply and cost limitations of cadaveric islet replacement. The California company ViaCyte is developing a pancreatic progenitor product from human stem cells that represents a renewable, cost-effective source of cells for islet replacement. Moreover, ViaCyte has developed a device that can contain the cells and is designed for implant under the skin. Clinical testing of this potential product is now underway, and initial results with low doses of cells indicate the procedure is safe.
In this project the Vancouver team aims to recruit patients with type 1 diabetes to examine if higher doses of the cells can restore normal control of blood glucose levels and reduce, or even eliminate, the need for insulin injections. The team consists of surgeon Dr. Garth Warnock, the first to successfully transplant donor islets in patients in Canada, and co-developer of the so-called “Edmonton Protocol” for islet transplant, clinicians Dr. David Thompson and Dr. Graydon Meneilly who are experts in diabetes management and will carefully follow the patients enrolled in the trial, Dr. Megan Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, and project leader Dr. Timothy Kieffer, an authority on cell therapy for diabetes whose laboratory research on stem cells provides strong scientific support for the trial. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes, putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 December 2016
31 December 2017
2016
Garth Warnock (C)
University of British Columbia
Subventions de soutien des essais cliniques
Kieffer
Cochercheur
Timothy Kieffer, Garth Warnock, Graydon Meneilly, Megan Levings, David Thompson, Bruce Verchere
82 000
A stem cell therapy for insulin replacement in patients with diabetes
Diabète
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921 and developed methods to purify it to provide a source for patients to inject. While life-sustaining, many patients with diabetes face a life-long routine of daily insulin injections and blood glucose measurements and suffer from several debilitating complications of the disease that severely reduce quality of life. Cell replacement therapy using islet cells obtained from organ donors has proven to be a highly effective treatment for diabetes. In fact, some islet recipients are completely insulin-independent five years after their transplant, and some even remain insulin-independent as long as ten years. However, use of this therapy is severely restricted due to a limited supply of donor organs and the high cost of the procedure. Stem cell-derived islet replacement can overcome both the supply and cost limitations of cadaveric islet replacement. The California company ViaCyte is developing a pancreatic progenitor product from human stem cells that represents a renewable, cost-effective source of cells for islet replacement. Moreover, ViaCyte has developed a device that can contain the cells and is designed for implant under the skin. Clinical testing of this potential product is now underway, and initial results with low doses of cells indicate the procedure is safe.
In this project the Vancouver team aims to recruit patients with type 1 diabetes to examine if higher doses of the cells can restore normal control of blood glucose levels and reduce, or even eliminate, the need for insulin injections. The team consists of surgeon Dr. Garth Warnock, the first to successfully transplant donor islets in patients in Canada, and co-developer of the so-called “Edmonton Protocol” for islet transplant, clinicians Dr. David Thompson and Dr. Graydon Meneilly who are experts in diabetes management and will carefully follow the patients enrolled in the trial, Dr. Megan Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, and project leader Dr. Timothy Kieffer, an authority on cell therapy for diabetes whose laboratory research on stem cells provides strong scientific support for the trial. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes, putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 December 2016
31 December 2017
2016
Graydon Meneilly (C)
University of British Columbia
Subventions de soutien des essais cliniques
Kieffer
Cochercheur
Timothy Kieffer, Garth Warnock, Graydon Meneilly, Megan Levings, David Thompson, Bruce Verchere
115 548
A stem cell therapy for insulin replacement in patients with diabetes
Diabète
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921 and developed methods to purify it to provide a source for patients to inject. While life-sustaining, many patients with diabetes face a life-long routine of daily insulin injections and blood glucose measurements and suffer from several debilitating complications of the disease that severely reduce quality of life. Cell replacement therapy using islet cells obtained from organ donors has proven to be a highly effective treatment for diabetes. In fact, some islet recipients are completely insulin-independent five years after their transplant, and some even remain insulin-independent as long as ten years. However, use of this therapy is severely restricted due to a limited supply of donor organs and the high cost of the procedure. Stem cell-derived islet replacement can overcome both the supply and cost limitations of cadaveric islet replacement. The California company ViaCyte is developing a pancreatic progenitor product from human stem cells that represents a renewable, cost-effective source of cells for islet replacement. Moreover, ViaCyte has developed a device that can contain the cells and is designed for implant under the skin. Clinical testing of this potential product is now underway, and initial results with low doses of cells indicate the procedure is safe.
In this project the Vancouver team aims to recruit patients with type 1 diabetes to examine if higher doses of the cells can restore normal control of blood glucose levels and reduce, or even eliminate, the need for insulin injections. The team consists of surgeon Dr. Garth Warnock, the first to successfully transplant donor islets in patients in Canada, and co-developer of the so-called “Edmonton Protocol” for islet transplant, clinicians Dr. David Thompson and Dr. Graydon Meneilly who are experts in diabetes management and will carefully follow the patients enrolled in the trial, Dr. Megan Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, and project leader Dr. Timothy Kieffer, an authority on cell therapy for diabetes whose laboratory research on stem cells provides strong scientific support for the trial. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes, putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 December 2016
31 December 2017
2016
Megan Levings (C)
University of British Columbia
Subventions de soutien des essais cliniques
Kieffer
Cochercheur
Timothy Kieffer, Garth Warnock, Graydon Meneilly, Megan Levings, David Thompson, Bruce Verchere
82 000
A stem cell therapy for insulin replacement in patients with diabetes
Diabète
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921 and developed methods to purify it to provide a source for patients to inject. While life-sustaining, many patients with diabetes face a life-long routine of daily insulin injections and blood glucose measurements and suffer from several debilitating complications of the disease that severely reduce quality of life. Cell replacement therapy using islet cells obtained from organ donors has proven to be a highly effective treatment for diabetes. In fact, some islet recipients are completely insulin-independent five years after their transplant, and some even remain insulin-independent as long as ten years. However, use of this therapy is severely restricted due to a limited supply of donor organs and the high cost of the procedure. Stem cell-derived islet replacement can overcome both the supply and cost limitations of cadaveric islet replacement. The California company ViaCyte is developing a pancreatic progenitor product from human stem cells that represents a renewable, cost-effective source of cells for islet replacement. Moreover, ViaCyte has developed a device that can contain the cells and is designed for implant under the skin. Clinical testing of this potential product is now underway, and initial results with low doses of cells indicate the procedure is safe.
In this project the Vancouver team aims to recruit patients with type 1 diabetes to examine if higher doses of the cells can restore normal control of blood glucose levels and reduce, or even eliminate, the need for insulin injections. The team consists of surgeon Dr. Garth Warnock, the first to successfully transplant donor islets in patients in Canada, and co-developer of the so-called “Edmonton Protocol” for islet transplant, clinicians Dr. David Thompson and Dr. Graydon Meneilly who are experts in diabetes management and will carefully follow the patients enrolled in the trial, Dr. Megan Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, and project leader Dr. Timothy Kieffer, an authority on cell therapy for diabetes whose laboratory research on stem cells provides strong scientific support for the trial. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes, putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 December 2016
31 December 2017
2016
Liam Brunham (P)
University of British Columbia
Recherche d’impact, clinical translation
Brunham
Chercheur principal
Liam Brunham, Glen Tibbits
50 000
Using human pluripotent stem-cell derived cardiomycytes to investigate the mechanisms of ibrutinib-induced atrial fibrilation
Cardiaque; fibrillation auriculaire
Ibrutinib is a new, highly effective medication used to treat blood cancers. However, up to 10% of patients receiving this medication develop an abnormal heart rhythm, called atrial fibrillation (AF) that can cause stroke. How Ibrutinib causes AF is unknown.
Human pluripotent stem cells (hPSCs) can be used to generate human heart cells (cardiomyocytes). We have shown that hPSC-derived cardiomyocytes are an excellent model system for studying drug-induced heart injury. The overall goal of this project is to use hPSC-derived cardiomyocytes to investigate the mechanisms of ibrutinib-induced AF.
We have developed unique technologies that will allow us to study this important question. This includes the ability to make cardiomyocytes representing the different heart chambers (atrial and ventricular), and to study electrical activity in cardiomyocytes. We have partnered with the Heart & Stroke Foundation of Canada for this work.
The outcomes of this study will be a novel stem cell-based model of ibrutinib-induced AF which will provide insights into the mechanisms of this side-effect, allowing us to predict which patients may be most sensitive to ibrutinib, and identify medications to treat or prevent AF in patients who receive ibrutinib, ultimately making treatment with this important new drug safer and more effective.
1 December 2016
31 December 2017
2016
Glen Tibbits (C)
Simon Fraser University
Recherche d’impact, clinical translation
Brunham
Cochercheur
Liam Brunham, Glen Tibbits
50 000
Using human pluripotent stem-cell derived cardiomycytes to investigate the mechanisms of ibrutinib-induced atrial fibrilation
Cardiaque; fibrillation auriculaire
Ibrutinib is a new, highly effective medication used to treat blood cancers. However, up to 10% of patients receiving this medication develop an abnormal heart rhythm, called atrial fibrillation (AF) that can cause stroke. How Ibrutinib causes AF is unknown.
Human pluripotent stem cells (hPSCs) can be used to generate human heart cells (cardiomyocytes). We have shown that hPSC-derived cardiomyocytes are an excellent model system for studying drug-induced heart injury. The overall goal of this project is to use hPSC-derived cardiomyocytes to investigate the mechanisms of ibrutinib-induced AF.
We have developed unique technologies that will allow us to study this important question. This includes the ability to make cardiomyocytes representing the different heart chambers (atrial and ventricular), and to study electrical activity in cardiomyocytes. We have partnered with the Heart & Stroke Foundation of Canada for this work.
The outcomes of this study will be a novel stem cell-based model of ibrutinib-induced AF which will provide insights into the mechanisms of this side-effect, allowing us to predict which patients may be most sensitive to ibrutinib, and identify medications to treat or prevent AF in patients who receive ibrutinib, ultimately making treatment with this important new drug safer and more effective.
1 December 2016
31 December 2017
2016
Jean-Philip Lumb (C)
Université McGill
Recherche d’impact, clinical translation
Crist
Cochercheur
Jean-Philip Lumb, Colin Crist
23 400
Activation of muscle stem cells by pharmacological inhibitors of elF2a phosphorylation
Muscle, muscles
There are few treatment options available for muscle wasting associated with cancer (cachexia), which affects roughly 50% of all cancer patients in Canada and has a major impact on morbidity and mortality. Cancer cachexia will benefit from the development of stem cell based therapies that promote the activity of endogenous muscle stem cells (MuSCs) to repair and contribute to new muscle. In healthy muscle, adult muscle stem cells are normally in a resting state and activate in response to muscle injury to repair muscle. Pharmacological approaches to activate muscle stem cells, or improve their intrinsic capacity to repair muscle are needed. We have demonstrated that normally resting muscle stem cells require tightly regulated levels of protein synthesis. Using genetic tools to inactivate pathways regulating protein synthesis, we demonstrate the spontaneous activation of muscle stem cells to generate new myofibres. These findings provide the conceptual basis for the current study, which aims to use pharmacological inhibition of pathways regulating protein synthesis to activate and improve the generation of myofibres from defective muscle stem cells in cachectic muscle. Using mouse models that permit the tracking of activated muscle stem cells by their expression of a red fluorescent protein, we will test known inhibitors of pathways regulating protein synthesis for their ability to activate muscle stem cells. Inhibitors that activate muscle stem cells are also expected to improve their activity under conditions that normally prevent their efficient contribution to repair, which will be tested in a preclinical mouse model of cancer cachexia.
1 December 2016
31 December 2017
2016
Colin Crist (P)
Jewish General Hospital
Recherche d’impact, clinical translation
Crist
Chercheur principal
Jean-Philip Lumb, Colin Crist
76 442
Activation of muscle stem cells by pharmacological inhibitors of elF2a phosphorylation
Muscle, muscles
There are few treatment options available for muscle wasting associated with cancer (cachexia), which affects roughly 50% of all cancer patients in Canada and has a major impact on morbidity and mortality. Cancer cachexia will benefit from the development of stem cell based therapies that promote the activity of endogenous muscle stem cells (MuSCs) to repair and contribute to new muscle. In healthy muscle, adult muscle stem cells are normally in a resting state and activate in response to muscle injury to repair muscle. Pharmacological approaches to activate muscle stem cells, or improve their intrinsic capacity to repair muscle are needed. We have demonstrated that normally resting muscle stem cells require tightly regulated levels of protein synthesis. Using genetic tools to inactivate pathways regulating protein synthesis, we demonstrate the spontaneous activation of muscle stem cells to generate new myofibres. These findings provide the conceptual basis for the current study, which aims to use pharmacological inhibition of pathways regulating protein synthesis to activate and improve the generation of myofibres from defective muscle stem cells in cachectic muscle. Using mouse models that permit the tracking of activated muscle stem cells by their expression of a red fluorescent protein, we will test known inhibitors of pathways regulating protein synthesis for their ability to activate muscle stem cells. Inhibitors that activate muscle stem cells are also expected to improve their activity under conditions that normally prevent their efficient contribution to repair, which will be tested in a preclinical mouse model of cancer cachexia.
1 December 2016
31 December 2017
2016
Bartha Knoppers (C)
Université McGill
Recherche d’impact, clinical translation
Germain
Cochercheur
Bartha Knoppers, Lucie Germain
10 000
Treatment of patients with corneal limbal stem cell deficiencies using epithelial grants
Oculaire
This project will complete our clinical trial and allows us to seek Health Canada approval for a new modality of treatment for corneal limbal stem cell deficiency (“LSCD”) using cell therapy. LSCD is a severe disease caused by damage/depletion of the corneal stem cells in the limbal region of the eye following trauma/disease. The epithelial tissue no longer regenerates resulting in chronic inflammation, conjunctivalization and vision loss. To treat LSCD patients, we have developed a tissue engineering technique involving massive expansion of epithelial cells in vitro to produce epithelial sheets for autologous transplantation (cultured epithelial corneal autografts – “CECA”). After thirty years of experience with skin substitutes using cultured epithelial autografts (“CEA”) on burn patients, we have successfully demonstrated the effectiveness of CECA (pre-clinical studies in animal models), and initiated a clinical trial approved by Health Canada (10 patients grafted with CECA on the 15 patients approved). This is the new treatment for which Health Canada approval will be sought. Our team of scientific researchers, clinicians and ethical/legal experts, with extra funding support from CHU de Québec Hospital Research Center, FRQS ThéCell Network, we will be the first in Canada to offer CECA treatment for unilaterally blind or vision impaired patients suffering from LSCD.
Le LOEX développe le génie tissulaire afin de reconstruire des tissus in vitro à des fins cliniques. La première application fût la culture de peau pour les grands brûlés. L’œil est recouvert par la cornée, qui nécessite les cellules souches limbiques, et dont la transparence est nécessaire à la vision. L’objectif du projet est de poursuivre l'essai clinique qui consiste à greffer une culture d’épithélium cornéen autologue (CECA) chez des patients souffrant d’une déficience unilatérale en cellules souches limbiques. Cette recherche translationnelle vise à finaliser l'essai clinique chez les premiers patients greffés avec CECA au Canada et à demander l'approbation de ce traitement à Santé Canada. Le projet consistera à prélever le tissu, à cultiver les cellules épithéliales du limbe in vitro sur un gel de fibrine qui sera greffé dans l’œil des patients. L’étude permettra d'effectuer la greffe des 5 derniers patients, de finaliser le suivi de 1 an de tous les patients, d’effectuer les analyses des résultats et de la faisabilité d’utiliser les CECA pour les indications proposées. Notre équipe multidisciplinaire permettra la translation clinique du produit du génie tissulaire: CECA. Nous serons les premiers au Canada à offrir ce traitement qui vise à améliorer la vision des patients.
1 December 2016
31 December 2017
2016
Lucie Germain (P)
Université Laval
Recherche d’impact, clinical translation
Germain
Chercheur principal
Bartha Knoppers, Lucie Germain
90 000
Treatment of patients with corneal limbal stem cell deficiencies using epithelial grants
Oculaire; déficit en cellules souches limbiques
This project will complete our clinical trial and allows us to seek Health Canada approval for a new modality of treatment for corneal limbal stem cell deficiency (“LSCD”) using cell therapy. LSCD is a severe disease caused by damage/depletion of the corneal stem cells in the limbal region of the eye following trauma/disease. The epithelial tissue no longer regenerates resulting in chronic inflammation, conjunctivalization and vision loss. To treat LSCD patients, we have developed a tissue engineering technique involving massive expansion of epithelial cells in vitro to produce epithelial sheets for autologous transplantation (cultured epithelial corneal autografts – “CECA”). After thirty years of experience with skin substitutes using cultured epithelial autografts (“CEA”) on burn patients, we have successfully demonstrated the effectiveness of CECA (pre-clinical studies in animal models), and initiated a clinical trial approved by Health Canada (10 patients grafted with CECA on the 15 patients approved). This is the new treatment for which Health Canada approval will be sought. Our team of scientific researchers, clinicians and ethical/legal experts, with extra funding support from CHU de Québec Hospital Research Center, FRQS ThéCell Network, we will be the first in Canada to offer CECA treatment for unilaterally blind or vision impaired patients suffering from LSCD.
Le LOEX développe le génie tissulaire afin de reconstruire des tissus in vitro à des fins cliniques. La première application fût la culture de peau pour les grands brûlés. L’œil est recouvert par la cornée, qui nécessite les cellules souches limbiques, et dont la transparence est nécessaire à la vision. L’objectif du projet est de poursuivre l'essai clinique qui consiste à greffer une culture d’épithélium cornéen autologue (CECA) chez des patients souffrant d’une déficience unilatérale en cellules souches limbiques. Cette recherche translationnelle vise à finaliser l'essai clinique chez les premiers patients greffés avec CECA au Canada et à demander l'approbation de ce traitement à Santé Canada. Le projet consistera à prélever le tissu, à cultiver les cellules épithéliales du limbe in vitro sur un gel de fibrine qui sera greffé dans l’œil des patients. L’étude permettra d'effectuer la greffe des 5 derniers patients, de finaliser le suivi de 1 an de tous les patients, d’effectuer les analyses des résultats et de la faisabilité d’utiliser les CECA pour les indications proposées. Notre équipe multidisciplinaire permettra la translation clinique du produit du génie tissulaire: CECA. Nous serons les premiers au Canada à offrir ce traitement qui vise à améliorer la vision des patients.
1 December 2016
31 December 2017
2016
James Johnson (P)
University of British Columbia
Recherche d’impact, clinical translation
Johnson
Chercheur principal
James Johnson
100 000
Image-based screening to enhance insulin production in human embryonic stem cells
Diabète
Islet transplantation has demonstrated that the replacement of insulin-producing β-cells is an effective means of restoring blood glucose control in patients with type 1 diabetes (T1D), especially in subjects at risk of severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors must be addressed. Remarkable progress has occurred in stem cell technology regarding clinical-grade insulin-producing cells with the capacity for limitless expansion; solving inadequate organ donor supply. Our group is currently conducting a first-in-human pilot phase 1/2 clinical trial to test ViaCyte’s (world leader in stem cell development) VC-01 combination product in a cohort of patients with T1D in Edmonton. This trial examines the ability of ViaCyte’s insulin-producing pancreatic endoderm cells (PEC) to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into National and Worldwide clinical practice. The objective of this SCN proposal is to use an innovative approach to bioengineer a retrievable, functionalized scaffold, that houses and supports long-term function of ViaCyte’s PEC cells to treat T1D. The Disease Team consists of Dr. James Shapiro, Dr. Gregory Korbutt and Dr. Carlo Montemagno. As a clinical scientist and Director of the Clinical Islet Transplant Program, Dr. Shapiro is internationally recognized for his pioneering contributions to the development of the ‘Edmonton Protocol’, and is currently leading thirteen clinical trials in islet, stem cell and liver transplantation. Co-PI, Dr. Korbutt, is the Scientific Director of the cGMP “Alberta Cell Therapy Manufacturing Facility” for cell and tissue production, with significant expertise in islet biology and transplantation. The Team has also established a productive collaboration with Dr. Montemagno, Director of the Ingenuity Lab Nanotechnology Accelerator, a multidisciplinary R&D initiative focused on groundbreaking nanotechnology advances. Strategies for further commercialization will be conducted with support from TEC Edmonton, whom has provided support in filing US and Canadian provisional patents for this technology. This research proposal has been developed by a group of investigators offering unique expertise in clinical islet transplantation and stem cell biology, as well as biomaterial engineering expertise. With an active clinical islet transplant program in Edmonton, a new cGMP facility for the clinical grade production of cells, and the bioactive scaffold design expertise of the Ingenuity’s Laboratory, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 December 2016
31 December 2017
2016
Timothy Kieffer (P)
University of British Columbia
Recherche d’impact, clinical translation
Kieffer
Chercheur principal
Timothy Kieffer
100 000
Biodistribution of differentiated stem cells following subcutaneous transplant
Diabète
Diabetes is a disease caused by insufficient production of the hormone insulin, resulting in elevated blood sugar levels and damage to several tissues leading to debilitating complications. Our overall goal is to develop a cell-based therapy for diabetes. We believe this can be achieved by the transplant of differentiated stem cells under the skin, whereby the cells take over the automatic production of insulin and control of blood sugar levels. We have developed cell culture procedures to generate large quantities of insulin-producing cells that can reverse diabetes in rodents. With support from JDRF, we are examining the effectiveness of this approach when transplanting the cells under the skin. We now plan to extend these studies by including genetically modified stem cells that will enable us to non-invasively image the cells following transplant in order to monitor their distribution throughout the body to confirm if the cells remain at the site of transplant. In addition, we will test a novel ‘kill-switch’ to determine if we can eliminate the transplanted cells by treatment with an otherwise harmless inducing agent. Collectively, these studies may provide important knowledge and added levels of safety to justify trying this therapeutic approach in humans with diabetes.
1 December 2016
31 December 2017
2016
Megan Levings (P)
University of British Columbia
Recherche d’impact, clinical translation
Levings
Chercheur principal
Megan Levings, Lori West
62 667
Garbage to Gold: Expansion of therapeutics regulatory T cells from discarded thymus
Sang; leucémie
For many patients with blood cancers, the only option for cure is hematopoietic stem cell transplantation (HSCT). Unfortunately, HSCT can cause a complication called graft-versus-host disease (GVHD), which happens when donor immune cells attack the patient’s healthy tissues. HSCT would be safer if we could prevent/reduce GVHD without affecting its anti-cancer action.
We are developing a novel cellular therapy with regulatory T cells (Treg) to use in combination with HSCT to prevent or treat GVHD. Early studies show promise, but using currently available protocols it is difficult and time-consuming to obtain enough Tregs with the correct properties.
We investigated the possibility of isolating Tregs from a new source: a gland called the thymus, which is discarded in children undergoing heart surgery. We found huge numbers of Tregs in the thymus and that thymic Tregs prevent GVHD in mice. In order to test thymic Tregs in a clinical trial in humans we now need to develop optimized and standard methods for large-scale expansion of thymic Tregs. We will work with STEMCELL Technologies to create new reagents and protocols to achieve this aim. This ground-work will be a key step in translating this approach to the bedside to test if delivering thymic Tregs can reduce GVHD.
1 December 2016
31 December 2017
2016
Lori West (C)
University of Alberta
Recherche d’impact, clinical translation
Levings
Cochercheur
Megan Levings, Lori West
37 333
Garbage to Gold: Expansion of therapeutics regulatory T cells from discarded thymus
Sang; leucémie
For many patients with blood cancers, the only option for cure is hematopoietic stem cell transplantation (HSCT). Unfortunately, HSCT can cause a complication called graft-versus-host disease (GVHD), which happens when donor immune cells attack the patient’s healthy tissues. HSCT would be safer if we could prevent/reduce GVHD without affecting its anti-cancer action.
We are developing a novel cellular therapy with regulatory T cells (Treg) to use in combination with HSCT to prevent or treat GVHD. Early studies show promise, but using currently available protocols it is difficult and time-consuming to obtain enough Tregs with the correct properties.
We investigated the possibility of isolating Tregs from a new source: a gland called the thymus, which is discarded in children undergoing heart surgery. We found huge numbers of Tregs in the thymus and that thymic Tregs prevent GVHD in mice. In order to test thymic Tregs in a clinical trial in humans we now need to develop optimized and standard methods for large-scale expansion of thymic Tregs. We will work with STEMCELL Technologies to create new reagents and protocols to achieve this aim. This ground-work will be a key step in translating this approach to the bedside to test if delivering thymic Tregs can reduce GVHD.
1 December 2016
31 December 2017
2016
Kelly McNagny (P)
University of British Columbia
Recherche d’impact, clinical translation
McNagny
Chercheur principal
Kelly McNagny
100 000
CAR-T cell therapy targeting tumor-specific modifications of Podocalyxin in triple negative breast cancer
Cancer du sein
Despite being more likely to receive chemotherapy, or surgery plus chemotherapy, the 5-year survival of triple-negative breast cancer (TNBC) patients remains below 65%1, and novel targeted approaches are urgently needed. Chimeric antigen receptors (CAR) combine the Fv portion of monoclonal antibodies (as a single chain Fv; scFv) and the intracellular signaling domain of immune co-stimulatory molecules and the CD3 molecule with the goal of activating T-cells in an antigen-specific manner, independent of their endogenous T cell receptor (TCR) repertoire2. CAR-T therapies targeting the surface molecule CD19 have shown exceptional promise in a limited number of clinical trials for B cell malignancies3, 4. Unfortunately, there are no obvious targets on the surface of TNBC cells that could be amenable to targeting by CAR-T cells. Previous work funded by the SCN demonstrated that the protein, Podocalyxin (Podxl) could be targeted by a naked antibody to reduce invasion and metastasis of TNBC cells in vivo, and that Podxl regulates their clonogenic potential (“stemness”) in vitro. Herein we propose to develop a novel humanized antibody (hPodo447) that recognizes a post-translational modification of Podxl found on TNBC cells (and a range of other tumors) as a targeting arm for CAR-T cell therapy.
1 December 2016
31 December 2017
2016
Paula Foster (C)
University of Western Ontario
Recherche d’impact, clinical translation
Viswanathan
Cochercheur
Sowmya Viswanathan, Mohit Kapoor, Paula Foster
47 000
Iron labeled-mesenchymal stromal cells for clinical tracking in amended Phase I trial in osteoarthritis patients
Ostéoarthrite, ostéo-arthrite
We have commenced a dose finding study using autologous mesenchymal stromal cells (MSCs) in Osteoarthritis (OA) patients, but have not identified an efficacious dose to date. To proceed further with a Phase II trial using allogenic MSCs, we need to identify a safe and efficacious MSC dose. Labeling MSCs with a Health Canada approved iron nanoparticle, Feraheme® (approved for anemia) will allow us to track persistence and localization of MSCs injected locally into the knee of OA patients, and will provide the necessary information to better determine dosing, frequency and use of carriers in the future. We propose to complete a study with sufficient animals to evaluate safety and efficacy of iron-labeled mouse MSCs. Iron and fluorescent-labeled MSCs are injected into the knee joints of mice, which have undergone a surgical injury to their meniscus to initiate arthritic inflammatory and degradation processes. Cells are tracked by magnetic resonance imaging (MRI) and confirmed by histology at the time of sacrifice; importantly, histology in other organs and blood chemistry tests will confirm safety of using iron-labeled MSCs. A pre-clinical trial consultation (CTA) with Health Canada confirmed their support for this experimental approach as the basis for initiating trials using iron-labeled MSCs.
1 December 2016
31 December 2017
2016
Mohit Kapoor (C)
University Health Network
Recherche d’impact, clinical translation
Viswanathan
Cochercheur
Sowmya Viswanathan, Mohit Kapoor, Paula Foster
5 000
Iron labeled-mesenchymal stromal cells for clinical tracking in amended Phase I trial in osteoarthritis patients
Ostéoarthrite, ostéo-arthrite
We have commenced a dose finding study using autologous mesenchymal stromal cells (MSCs) in Osteoarthritis (OA) patients, but have not identified an efficacious dose to date. To proceed further with a Phase II trial using allogenic MSCs, we need to identify a safe and efficacious MSC dose. Labeling MSCs with a Health Canada approved iron nanoparticle, Feraheme® (approved for anemia) will allow us to track persistence and localization of MSCs injected locally into the knee of OA patients, and will provide the necessary information to better determine dosing, frequency and use of carriers in the future. We propose to complete a study with sufficient animals to evaluate safety and efficacy of iron-labeled mouse MSCs. Iron and fluorescent-labeled MSCs are injected into the knee joints of mice, which have undergone a surgical injury to their meniscus to initiate arthritic inflammatory and degradation processes. Cells are tracked by magnetic resonance imaging (MRI) and confirmed by histology at the time of sacrifice; importantly, histology in other organs and blood chemistry tests will confirm safety of using iron-labeled MSCs. A pre-clinical trial consultation (CTA) with Health Canada confirmed their support for this experimental approach as the basis for initiating trials using iron-labeled MSCs.
1 December 2016
31 December 2017
2016
Sowmya Viswanathan (P)
University Health Network
Recherche d’impact, clinical translation
Viswanathan
Chercheur principal
Sowmya Viswanathan, Mohit Kapoor, Paula Foster
48 000
Iron labeled-mesenchymal stromal cells for clinical tracking in amended Phase I trial in osteoarthritis patients
Ostéoarthrite, ostéo-arthrite
We have commenced a dose finding study using autologous mesenchymal stromal cells (MSCs) in Osteoarthritis (OA) patients, but have not identified an efficacious dose to date. To proceed further with a Phase II trial using allogenic MSCs, we need to identify a safe and efficacious MSC dose. Labeling MSCs with a Health Canada approved iron nanoparticle, Feraheme® (approved for anemia) will allow us to track persistence and localization of MSCs injected locally into the knee of OA patients, and will provide the necessary information to better determine dosing, frequency and use of carriers in the future. We propose to complete a study with sufficient animals to evaluate safety and efficacy of iron-labeled mouse MSCs. Iron and fluorescent-labeled MSCs are injected into the knee joints of mice, which have undergone a surgical injury to their meniscus to initiate arthritic inflammatory and degradation processes. Cells are tracked by magnetic resonance imaging (MRI) and confirmed by histology at the time of sacrifice; importantly, histology in other organs and blood chemistry tests will confirm safety of using iron-labeled MSCs. A pre-clinical trial consultation (CTA) with Health Canada confirmed their support for this experimental approach as the basis for initiating trials using iron-labeled MSCs.
We have developed a first-in-class umbilical cord blood (UCB)-derived hematopoietic stem cell (HSC) expansion platform that combines a “fed-batch” (FB) bioprocess with the HSC-stimulating small molecule UM171. This process is in a Phase 1-2 clinical trial. Our next step is to enhance the clinical efficacy and commercial potential of the grafts produced from the FB + UM171 bioprocess by reducing production costs and increasing HSC expansion outputs. We propose to accomplish this by optimizing medium additives such as cytokines and novel proprietary molecules using powerful statistical design strategies. Cell output will be assessed by flow cytometry analysis for HSC-associated phenotypes (CD34+CD45RA-CD90+CD201-) and functional cell engraftment in immunocompromised mice. We anticipate that this medium optimization process will double our HSC output in shorter culture periods (culture time recently shortened from 12 to 7 days), thereby reducing our cost-of-goods to less than $5000 per patient. This goal would give our Canadian Biotech partner, ExCellThera, a dramatic advantage over our international competitors who typically perform cultures over several weeks at a cost-per-culture exceeding $40,000. At the end of our 1 year funding period the conditions established in this study will be incorporated into the Phase 1-2 clinical trial for the use of expanded HSCs to treat leukemia.
We have developed a first-in-class umbilical cord blood (UCB)-derived hematopoietic stem cell (HSC) expansion platform that combines a “fed-batch” (FB) bioprocess with the HSC-stimulating small molecule UM171. This process is in a Phase 1-2 clinical trial. Our next step is to enhance the clinical efficacy and commercial potential of the grafts produced from the FB + UM171 bioprocess by reducing production costs and increasing HSC expansion outputs. We propose to accomplish this by optimizing medium additives such as cytokines and novel proprietary molecules using powerful statistical design strategies. Cell output will be assessed by flow cytometry analysis for HSC-associated phenotypes (CD34+CD45RA-CD90+CD201-) and functional cell engraftment in immunocompromised mice. We anticipate that this medium optimization process will double our HSC output in shorter culture periods (culture time recently shortened from 12 to 7 days), thereby reducing our cost-of-goods to less than $5000 per patient. This goal would give our Canadian Biotech partner, ExCellThera, a dramatic advantage over our international competitors who typically perform cultures over several weeks at a cost-per-culture exceeding $40,000. At the end of our 1 year funding period the conditions established in this study will be incorporated into the Phase 1-2 clinical trial for the use of expanded HSCs to treat leukemia.
We have developed a first-in-class umbilical cord blood (UCB)-derived hematopoietic stem cell (HSC) expansion platform that combines a “fed-batch” (FB) bioprocess with the HSC-stimulating small molecule UM171. This process is in a Phase 1-2 clinical trial. Our next step is to enhance the clinical efficacy and commercial potential of the grafts produced from the FB + UM171 bioprocess by reducing production costs and increasing HSC expansion outputs. We propose to accomplish this by optimizing medium additives such as cytokines and novel proprietary molecules using powerful statistical design strategies. Cell output will be assessed by flow cytometry analysis for HSC-associated phenotypes (CD34+CD45RA-CD90+CD201-) and functional cell engraftment in immunocompromised mice. We anticipate that this medium optimization process will double our HSC output in shorter culture periods (culture time recently shortened from 12 to 7 days), thereby reducing our cost-of-goods to less than $5000 per patient. This goal would give our Canadian Biotech partner, ExCellThera, a dramatic advantage over our international competitors who typically perform cultures over several weeks at a cost-per-culture exceeding $40,000. At the end of our 1 year funding period the conditions established in this study will be incorporated into the Phase 1-2 clinical trial for the use of expanded HSCs to treat leukemia.
1 December 2016
31 December 2017
2016
Kristin Hope (P)
McMaster University
Recherche d’impact, commercialisation
Hope
Chercheur principal
Kristin Hope
100 000
Methods and compositions for expansion of human hematopoietic stem and progenitor cells
Sang
Lifesaving bone-marrow stem cell transplantations have been in clinical use for the treatment of leukemias and blood diseases for decades but are challenged by the need to find immune-matched donors. Umbilical cord blood is an important alternative source of clinically superior stem cells but has limited use in transplants because there are too few stem cells in a single cord. To overcome these challenges, this project will capitalize on our recent discovery of a gene (Musashi-2) that helps human blood stem cells expand in number in a laboratory culture dish. Our work has identified a chemical inhibitor that mimics the MSI2’s effects and promotes stem cell expansion. The current proposal aims to solidify that CYP1B1 is a viable target and important facilitator of stem cell expansion and to identify additional small molecule compounds with even more significant stem cell promoting effects. This proposal aligns with the Commercialization Impact Program as its goal is to deliver an improved stem cell product for clinical transplantation purposes. By enabling the use of clinically superior, more readily available cord blood stem cells our research provides great potential for immediate benefits to Canadians by allowing many more patients to receive the lifesaving transplants they need.
1 December 2016
31 December 2017
2016
Joanne Matsubara (P)
University of British Columbia
Recherche d’impact, commercialisation
Matsubara
Chercheur principal
Joanne Matsubara, Marinko Sarunic
85 502
Treating advanced retinal degeneration - rebuilding multiple co-dependent retinal layers with a single injection of stem cell-derived graft
Oculaire
Despite dozens of clinical trials (and countless animal trials) to regenerate the retina with stem cells, none have solved the challenge successfully. This is because the retina has many layers, and all layers are necessary in order to restore vision in patients with advanced retinal degeneration – ~1M patients in Canada and >100M worldwide. Here, we developed a strategy that utilizes a magnetic implant, atraumatically placed behind the eye, to stratify a suspension mixture of subretinal graft (including stem-cell-derived RPE and photoreceptors) into correct orientation and layering resulting in replacement of the lost retinal layers. This is all performed with standard outpatient retinal surgery techniques and infrastructure.
The SCN Commercialization Impact Research Agreement grant, Category 2, would enable final data acquisition within the 12-month funding window for completion of a strong and comprehensive international PCT patent filing covering this technology – most importantly, including transplantation trials of dual-layer and tri-layer graft into our rabbit animal models.
The UBC new venture, VisuCyte Therapeutics, was founded in 2015 to pursue commercialization of this technology. After PCT patent filing, VisuCyte, through UBC’s Accelerator Program, will seek venture capital funds to further research and development towards clinical commercialization.
1 December 2016
31 December 2017
2016
Marinko Sarunic (C)
Simon Fraser University
Recherche d’impact, commercialisation
Matsubara
Cochercheur
Joanne Matsubara, Marinko Sarunic
14 000
Treating advanced retinal degeneration - rebuilding multiple co-dependent retinal layers with a single injection of stem cell-derived graft
Oculaire
Despite dozens of clinical trials (and countless animal trials) to regenerate the retina with stem cells, none have solved the challenge successfully. This is because the retina has many layers, and all layers are necessary in order to restore vision in patients with advanced retinal degeneration – ~1M patients in Canada and >100M worldwide. Here, we developed a strategy that utilizes a magnetic implant, atraumatically placed behind the eye, to stratify a suspension mixture of subretinal graft (including stem-cell-derived RPE and photoreceptors) into correct orientation and layering resulting in replacement of the lost retinal layers. This is all performed with standard outpatient retinal surgery techniques and infrastructure.
The SCN Commercialization Impact Research Agreement grant, Category 2, would enable final data acquisition within the 12-month funding window for completion of a strong and comprehensive international PCT patent filing covering this technology – most importantly, including transplantation trials of dual-layer and tri-layer graft into our rabbit animal models.
The UBC new venture, VisuCyte Therapeutics, was founded in 2015 to pursue commercialization of this technology. After PCT patent filing, VisuCyte, through UBC’s Accelerator Program, will seek venture capital funds to further research and development towards clinical commercialization.
1 December 2016
31 December 2017
2016
Ian Rogers (P)
Sinai Health System
Recherche d’impact, commercialisation
Rogers
Chercheur principal
Ian Rogers
90 811
Improving efficacy and economics of kidney disease therapies using iPS cells
Néphropathie, maladie du rein
We are focused on new treatments for kidney diseases by developing a large, diverse bank of cells (with an emphasis on age related effects) that can be used as targets for drug screens. We will develop induced pluripotent stem (iPS) cells as ‘informative’ cells for drug screening. Specifically, donor urine-cells will be used to produce iPS cells that can then be differentiated into renal cell targets. Many studies have determined that iPS cells are the gateway to personalized medicine. Each iPS cell line retains characteristics of donor origin and responds to drugs in a manner similar to the donor themselves, thus allowing for efficient, population-like drug screens that are carried out in a dish. This will help to identify effective and safe drugs rapidly thus reducing the cost of drug development and reducing the side effects observed with many drugs on the market. In partnership with Mt. Sinai Hospital and AstraZeneca we propose to develop a bank of human iPS cell lines to be used as targets in drug screens aimed at novel drug development and for finding new indications for known drugs. These iPS cell lines will be made available to industry and academic research centers.
1 December 2016
31 December 2017
2016
Mark Ungrin (P)
University of Calgary
Recherche d’impact, commercialisation
Ungrin
Chercheur principal
Mark Ungrin
100 000
Scalable production of engineered microtissues
Fabrication
This project builds on my successful AggreWell technology, developing and validating an AggreWell bioreactor. Continuing in the theme of broad accessibility that has made the AggreWell system a success, we will provide the large and growing community of AggreWell users around the world with an avenue to scale their procedures to the quantities required for animal / preclinical trials, without a need to invest in expensive equipment or acquire expertise in e.g. stirred suspension bioreactor culture. A Canadian success story, invented in Canada and commercialized by industry partner STEMCELL Technologies of Vancouver, the AggreWell system is cited in over 350 publications and growing rapidly. This project will expand this trajectory of scientific and commercial success, delivering economic (job creation, tax on revenues) and in the longer term healthcare (accelerated progress towards cell based therapies for conditions such as diabetes) benefits to Canadians. My long and successful relationship with STEMCELL and their familiarity with AggreWell manufacturing and international sales will ensure the results of this research project are a commercial success.
1 December 2016
31 December 2017
2016
Stephanie Willerth (P)
University of Victoria
Recherche d’impact, commercialisation
Willerth
Chercheur principal
Stephanie Willerth
100 000
3D bioprinting of neural tissue from human pluripotent stem cells
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Paul Frankland (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 554
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
David Kaplan (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Ann Yeh (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Douglas Munoz (C)
Queen's University
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Freda Miller (P)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Chercheur principal
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Cindi Morshead (C)
University of Toronto
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Neural, neuronal, neurale, neuronale, neurales, neuronales; sclérose en plaques
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Wolfram Tetzlaff (C)
University of British Columbia
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Wolfram Tetzlaff, Jing Wang, Cindi Morshead, Donald Mabbott, Douglas Munoz, Ann Yeh, David Kaplan, Paul Frankland
55 556
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 December 2016
31 December 2017
2016
Guy Sauvageau (C)
Université de Montréal
Équipes de recherche sur les maladies
Marinier
Cochercheur
Anne Marinier, Keith Humphries, James Shapiro, Connie Eaves, Guy Sauvageau
49 992
Development of hematopoietic stem cell expanding molecules towards the ideal transplant
Sang
Hematopoietic stem cell (HSC) transplantation (HSCT) is based on the transfer of HSCs from donors’ mobilized peripheral blood or bone marrow to recipients. As HLA matching is critical for HSCT and 30% of patients lack an HLA identical donor, cord blood (CB) is used as an alternative source of HSCs. Despite major assets associated with CB transplants, such as the high efficacy of anti-disease (leukemia, lymphoma) effect and low incidence of chronic graft versus host disease, the low cell dose in CB units linked to high transplant related mortality precludes their widespread use.
With the general objective of developing the best protocol for HSCT, we searched for strategies aimed at expanding CB HSCs and discovered the molecule UM171, which uniquely provided expanded CB units that are currently tested in a Phase I/II clinical trial. Although significantly improved after UM171 treatment, small CB grafts would benefit from the effect of an additional molecule that further expands stem and progenitor cells. To that end, we recently identified UM092, for which initial structure-activity relationship (SAR) studies demonstrated a potential for further structural optimization, an activity proposed in this agreement. Following pre-clinical development activities with the optimised analog including in vivo pharmacokinetics and toxicity evaluation, the GMP production of the molecule will then be undertaken, delivering material ready for extended phase II clinical studies.
Based on our experience in developing UM171, a Canadian team consisting of chemists with strong industrial expertise and renowned stem cell biologists was assembled to efficiently develop SAR and identify the best complements to UM171. Experts in drug metabolism/pharmacokinetics and toxicology have also joined the team for characterization of the new molecules and the expanded cellular material, along with cell therapy specialists to deliver the final expanded cell product. Supported by committed partners such as ExcellThera, to which the optimised UM092 will be out-licensed for the development of our novel HSCT technology, StemCell Technologies, as the likely commercial supplier of the novel compounds for research, Hôpital Charles-Le-Moyne, for CBs supplying, and various funding agencies, this team is in a strong position to advance to clinical studies this transformative technology that will increase CB accessibility to a larger number of patients from Canada and abroad once on the market. This will undoubtedly lead to a paradigm shift in the field of HSCT with CB emerging as the best HSC source for the treatment of hematologic malignancies as well as non-oncology indications.
1 December 2016
31 December 2017
2016
Anne Marinier (P)
Université de Montréal
Équipes de recherche sur les maladies
Marinier
Chercheur principal
Anne Marinier, Keith Humphries, James Shapiro, Connie Eaves, Guy Sauvageau
405 557
Development of hematopoietic stem cell expanding molecules towards the ideal transplant
Sang
Hematopoietic stem cell (HSC) transplantation (HSCT) is based on the transfer of HSCs from donors’ mobilized peripheral blood or bone marrow to recipients. As HLA matching is critical for HSCT and 30% of patients lack an HLA identical donor, cord blood (CB) is used as an alternative source of HSCs. Despite major assets associated with CB transplants, such as the high efficacy of anti-disease (leukemia, lymphoma) effect and low incidence of chronic graft versus host disease, the low cell dose in CB units linked to high transplant related mortality precludes their widespread use.
With the general objective of developing the best protocol for HSCT, we searched for strategies aimed at expanding CB HSCs and discovered the molecule UM171, which uniquely provided expanded CB units that are currently tested in a Phase I/II clinical trial. Although significantly improved after UM171 treatment, small CB grafts would benefit from the effect of an additional molecule that further expands stem and progenitor cells. To that end, we recently identified UM092, for which initial structure-activity relationship (SAR) studies demonstrated a potential for further structural optimization, an activity proposed in this agreement. Following pre-clinical development activities with the optimised analog including in vivo pharmacokinetics and toxicity evaluation, the GMP production of the molecule will then be undertaken, delivering material ready for extended phase II clinical studies.
Based on our experience in developing UM171, a Canadian team consisting of chemists with strong industrial expertise and renowned stem cell biologists was assembled to efficiently develop SAR and identify the best complements to UM171. Experts in drug metabolism/pharmacokinetics and toxicology have also joined the team for characterization of the new molecules and the expanded cellular material, along with cell therapy specialists to deliver the final expanded cell product. Supported by committed partners such as ExcellThera, to which the optimised UM092 will be out-licensed for the development of our novel HSCT technology, StemCell Technologies, as the likely commercial supplier of the novel compounds for research, Hôpital Charles-Le-Moyne, for CBs supplying, and various funding agencies, this team is in a strong position to advance to clinical studies this transformative technology that will increase CB accessibility to a larger number of patients from Canada and abroad once on the market. This will undoubtedly lead to a paradigm shift in the field of HSCT with CB emerging as the best HSC source for the treatment of hematologic malignancies as well as non-oncology indications.
1 December 2016
31 December 2017
2016
Connie Eaves (C)
University of British Columbia
Équipes de recherche sur les maladies
Marinier
Cochercheur
Anne Marinier, Keith Humphries, James Shapiro, Connie Eaves, Guy Sauvageau
30 750
Development of hematopoietic stem cell expanding molecules towards the ideal transplant
Sang
Hematopoietic stem cell (HSC) transplantation (HSCT) is based on the transfer of HSCs from donors’ mobilized peripheral blood or bone marrow to recipients. As HLA matching is critical for HSCT and 30% of patients lack an HLA identical donor, cord blood (CB) is used as an alternative source of HSCs. Despite major assets associated with CB transplants, such as the high efficacy of anti-disease (leukemia, lymphoma) effect and low incidence of chronic graft versus host disease, the low cell dose in CB units linked to high transplant related mortality precludes their widespread use.
With the general objective of developing the best protocol for HSCT, we searched for strategies aimed at expanding CB HSCs and discovered the molecule UM171, which uniquely provided expanded CB units that are currently tested in a Phase I/II clinical trial. Although significantly improved after UM171 treatment, small CB grafts would benefit from the effect of an additional molecule that further expands stem and progenitor cells. To that end, we recently identified UM092, for which initial structure-activity relationship (SAR) studies demonstrated a potential for further structural optimization, an activity proposed in this agreement. Following pre-clinical development activities with the optimised analog including in vivo pharmacokinetics and toxicity evaluation, the GMP production of the molecule will then be undertaken, delivering material ready for extended phase II clinical studies.
Based on our experience in developing UM171, a Canadian team consisting of chemists with strong industrial expertise and renowned stem cell biologists was assembled to efficiently develop SAR and identify the best complements to UM171. Experts in drug metabolism/pharmacokinetics and toxicology have also joined the team for characterization of the new molecules and the expanded cellular material, along with cell therapy specialists to deliver the final expanded cell product. Supported by committed partners such as ExcellThera, to which the optimised UM092 will be out-licensed for the development of our novel HSCT technology, StemCell Technologies, as the likely commercial supplier of the novel compounds for research, Hôpital Charles-Le-Moyne, for CBs supplying, and various funding agencies, this team is in a strong position to advance to clinical studies this transformative technology that will increase CB accessibility to a larger number of patients from Canada and abroad once on the market. This will undoubtedly lead to a paradigm shift in the field of HSCT with CB emerging as the best HSC source for the treatment of hematologic malignancies as well as non-oncology indications.
1 December 2016
31 December 2017
2016
Keith Humphries (C)
University of British Columbia
Équipes de recherche sur les maladies
Marinier
Cochercheur
Anne Marinier, Keith Humphries, James Shapiro, Connie Eaves, Guy Sauvageau
13 700
Development of hematopoietic stem cell expanding molecules towards the ideal transplant
Sang
Hematopoietic stem cell (HSC) transplantation (HSCT) is based on the transfer of HSCs from donors’ mobilized peripheral blood or bone marrow to recipients. As HLA matching is critical for HSCT and 30% of patients lack an HLA identical donor, cord blood (CB) is used as an alternative source of HSCs. Despite major assets associated with CB transplants, such as the high efficacy of anti-disease (leukemia, lymphoma) effect and low incidence of chronic graft versus host disease, the low cell dose in CB units linked to high transplant related mortality precludes their widespread use.
With the general objective of developing the best protocol for HSCT, we searched for strategies aimed at expanding CB HSCs and discovered the molecule UM171, which uniquely provided expanded CB units that are currently tested in a Phase I/II clinical trial. Although significantly improved after UM171 treatment, small CB grafts would benefit from the effect of an additional molecule that further expands stem and progenitor cells. To that end, we recently identified UM092, for which initial structure-activity relationship (SAR) studies demonstrated a potential for further structural optimization, an activity proposed in this agreement. Following pre-clinical development activities with the optimised analog including in vivo pharmacokinetics and toxicity evaluation, the GMP production of the molecule will then be undertaken, delivering material ready for extended phase II clinical studies.
Based on our experience in developing UM171, a Canadian team consisting of chemists with strong industrial expertise and renowned stem cell biologists was assembled to efficiently develop SAR and identify the best complements to UM171. Experts in drug metabolism/pharmacokinetics and toxicology have also joined the team for characterization of the new molecules and the expanded cellular material, along with cell therapy specialists to deliver the final expanded cell product. Supported by committed partners such as ExcellThera, to which the optimised UM092 will be out-licensed for the development of our novel HSCT technology, StemCell Technologies, as the likely commercial supplier of the novel compounds for research, Hôpital Charles-Le-Moyne, for CBs supplying, and various funding agencies, this team is in a strong position to advance to clinical studies this transformative technology that will increase CB accessibility to a larger number of patients from Canada and abroad once on the market. This will undoubtedly lead to a paradigm shift in the field of HSCT with CB emerging as the best HSC source for the treatment of hematologic malignancies as well as non-oncology indications.
1 December 2016
31 December 2017
2016
Timothy Kieffer (P)
University of British Columbia
Équipes de recherche sur les maladies
Kieffer
Chercheur principal
Timothy Kieffer, James Johnson, Bruce Verchere, Francis Lynn, Brad Hoffman
125 000
Optimizing stem cell derived beta-cell therapy for diabetes
Diabète
Diabetes, or high blood sugar, results from a deficit in the function of a small population of highly specialized cells in the pancreas, called -cells, that produce the hormone insulin. Fortunately, the Canadian discovery of insulin allows patients with diabetes to survive by daily injections. Despite this, patients still suffer from debilitating complications that significantly impact quality of life and reduce lifespan due to imprecise regulation of blood sugar levels. Canadians demonstrated that transplant of -cells obtained from organ donors can completely eliminate the need for insulin injections. However, this procedure is limited to less than 1% of the millions who suffer from diabetes because of a shortage of organ donors.
Laboratories around the world have made significant strides towards producing unlimited quantities of -like cells from stem cells. One company has even started clinical trials, transplanting cells derived from stem cells into more than a dozen diabetic patients thus far. While this is significant and encouraging progress, unanswered questions prevent us from cultivating fully functional -cells. The goal of our research program is to identify why our current protocols fail to generate functional -cells and to develop ways to surmount this barrier to enable the potential cure for diabetes. These cells will also be useful in researching how diabetes occurs, which could lead to new ways of preventing the disease.
Team leader Dr. Kieffer has worked closely with industry collaborators to develop and test what many believe are presently the world’s best protocols for coaxing stem cells towards -cells. He has been joined in these efforts by Dr. Johnson, a leading authority on the pathways that define mature -cells and sophisticated imaging techniques. Dr. Lynn is also an expert in stem cell culture and studies how -cells develop and mature in the body, which will be critical knowledge for duplicating this process in the laboratory. Dr. Hoffman studies the complex genetic interactions that orchestrate -cell development and uses powerful sequencing techniques to ‘fingerprint’ the genetic code of mature -cells and those generated in our laboratories. Both functional and gene analysis technologies will be critical to pinpoint deficits in currently produced cells, and also to validate when we successfully produce mature -cells. This team, with its highly complementary skills, is poised to develop methods to manufacture mature -cells for what promises to be a new paradigm in diabetes treatment.
1 December 2016
31 December 2017
2016
James Johnson (C)
University of British Columbia
Équipes de recherche sur les maladies
Kieffer
Cochercheur
Timothy Kieffer, James Johnson, Bruce Verchere, Francis Lynn, Brad Hoffman
125 000
Optimizing stem cell derived beta-cell therapy for diabetes
Diabète
Diabetes, or high blood sugar, results from a deficit in the function of a small population of highly specialized cells in the pancreas, called -cells, that produce the hormone insulin. Fortunately, the Canadian discovery of insulin allows patients with diabetes to survive by daily injections. Despite this, patients still suffer from debilitating complications that significantly impact quality of life and reduce lifespan due to imprecise regulation of blood sugar levels. Canadians demonstrated that transplant of -cells obtained from organ donors can completely eliminate the need for insulin injections. However, this procedure is limited to less than 1% of the millions who suffer from diabetes because of a shortage of organ donors.
Laboratories around the world have made significant strides towards producing unlimited quantities of -like cells from stem cells. One company has even started clinical trials, transplanting cells derived from stem cells into more than a dozen diabetic patients thus far. While this is significant and encouraging progress, unanswered questions prevent us from cultivating fully functional -cells. The goal of our research program is to identify why our current protocols fail to generate functional -cells and to develop ways to surmount this barrier to enable the potential cure for diabetes. These cells will also be useful in researching how diabetes occurs, which could lead to new ways of preventing the disease.
Team leader Dr. Kieffer has worked closely with industry collaborators to develop and test what many believe are presently the world’s best protocols for coaxing stem cells towards -cells. He has been joined in these efforts by Dr. Johnson, a leading authority on the pathways that define mature -cells and sophisticated imaging techniques. Dr. Lynn is also an expert in stem cell culture and studies how -cells develop and mature in the body, which will be critical knowledge for duplicating this process in the laboratory. Dr. Hoffman studies the complex genetic interactions that orchestrate -cell development and uses powerful sequencing techniques to ‘fingerprint’ the genetic code of mature -cells and those generated in our laboratories. Both functional and gene analysis technologies will be critical to pinpoint deficits in currently produced cells, and also to validate when we successfully produce mature -cells. This team, with its highly complementary skills, is poised to develop methods to manufacture mature -cells for what promises to be a new paradigm in diabetes treatment.
1 December 2016
31 December 2017
2016
Francis Lynn (C)
University of British Columbia
Équipes de recherche sur les maladies
Kieffer
Cochercheur
Timothy Kieffer, James Johnson, Bruce Verchere, Francis Lynn, Brad Hoffman
125 000
Optimizing stem cell derived beta-cell therapy for diabetes
Diabète
Diabetes, or high blood sugar, results from a deficit in the function of a small population of highly specialized cells in the pancreas, called -cells, that produce the hormone insulin. Fortunately, the Canadian discovery of insulin allows patients with diabetes to survive by daily injections. Despite this, patients still suffer from debilitating complications that significantly impact quality of life and reduce lifespan due to imprecise regulation of blood sugar levels. Canadians demonstrated that transplant of -cells obtained from organ donors can completely eliminate the need for insulin injections. However, this procedure is limited to less than 1% of the millions who suffer from diabetes because of a shortage of organ donors.
Laboratories around the world have made significant strides towards producing unlimited quantities of -like cells from stem cells. One company has even started clinical trials, transplanting cells derived from stem cells into more than a dozen diabetic patients thus far. While this is significant and encouraging progress, unanswered questions prevent us from cultivating fully functional -cells. The goal of our research program is to identify why our current protocols fail to generate functional -cells and to develop ways to surmount this barrier to enable the potential cure for diabetes. These cells will also be useful in researching how diabetes occurs, which could lead to new ways of preventing the disease.
Team leader Dr. Kieffer has worked closely with industry collaborators to develop and test what many believe are presently the world’s best protocols for coaxing stem cells towards -cells. He has been joined in these efforts by Dr. Johnson, a leading authority on the pathways that define mature -cells and sophisticated imaging techniques. Dr. Lynn is also an expert in stem cell culture and studies how -cells develop and mature in the body, which will be critical knowledge for duplicating this process in the laboratory. Dr. Hoffman studies the complex genetic interactions that orchestrate -cell development and uses powerful sequencing techniques to ‘fingerprint’ the genetic code of mature -cells and those generated in our laboratories. Both functional and gene analysis technologies will be critical to pinpoint deficits in currently produced cells, and also to validate when we successfully produce mature -cells. This team, with its highly complementary skills, is poised to develop methods to manufacture mature -cells for what promises to be a new paradigm in diabetes treatment.
1 December 2016
31 December 2017
2016
Brad Hoffman (C)
University of British Columbia
Équipes de recherche sur les maladies
Kieffer
Cochercheur
Timothy Kieffer, James Johnson, Bruce Verchere, Francis Lynn, Brad Hoffman
125 000
Optimizing stem cell derived beta-cell therapy for diabetes
Diabète
Diabetes, or high blood sugar, results from a deficit in the function of a small population of highly specialized cells in the pancreas, called -cells, that produce the hormone insulin. Fortunately, the Canadian discovery of insulin allows patients with diabetes to survive by daily injections. Despite this, patients still suffer from debilitating complications that significantly impact quality of life and reduce lifespan due to imprecise regulation of blood sugar levels. Canadians demonstrated that transplant of -cells obtained from organ donors can completely eliminate the need for insulin injections. However, this procedure is limited to less than 1% of the millions who suffer from diabetes because of a shortage of organ donors.
Laboratories around the world have made significant strides towards producing unlimited quantities of -like cells from stem cells. One company has even started clinical trials, transplanting cells derived from stem cells into more than a dozen diabetic patients thus far. While this is significant and encouraging progress, unanswered questions prevent us from cultivating fully functional -cells. The goal of our research program is to identify why our current protocols fail to generate functional -cells and to develop ways to surmount this barrier to enable the potential cure for diabetes. These cells will also be useful in researching how diabetes occurs, which could lead to new ways of preventing the disease.
Team leader Dr. Kieffer has worked closely with industry collaborators to develop and test what many believe are presently the world’s best protocols for coaxing stem cells towards -cells. He has been joined in these efforts by Dr. Johnson, a leading authority on the pathways that define mature -cells and sophisticated imaging techniques. Dr. Lynn is also an expert in stem cell culture and studies how -cells develop and mature in the body, which will be critical knowledge for duplicating this process in the laboratory. Dr. Hoffman studies the complex genetic interactions that orchestrate -cell development and uses powerful sequencing techniques to ‘fingerprint’ the genetic code of mature -cells and those generated in our laboratories. Both functional and gene analysis technologies will be critical to pinpoint deficits in currently produced cells, and also to validate when we successfully produce mature -cells. This team, with its highly complementary skills, is poised to develop methods to manufacture mature -cells for what promises to be a new paradigm in diabetes treatment.
1 December 2016
31 December 2017
2016
Bruce Verchere (P)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Chercheur principal
Bruce Verchere, Francis Lynn, Guy Sauvageau, Timothy Kieffer, Megan Levings
200 000
Genetic manipulation of hESC-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 December 2016
31 December 2017
2016
Francis Lynn (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Guy Sauvageau, Timothy Kieffer, Megan Levings
160 000
Genetic manipulation of hESC-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 December 2016
31 December 2017
2016
Timothy Kieffer (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Guy Sauvageau, Timothy Kieffer, Megan Levings
65 000
Genetic manipulation of hESC-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 December 2016
31 December 2017
2016
Megan Levings (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Guy Sauvageau, Timothy Kieffer, Megan Levings
65 000
Genetic manipulation of hESC-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 December 2016
31 December 2017
2016
Armand Keating (C)
University Health Network
Équipes de recherche sur les maladies
Nagy
Cochercheur
Andras Nagy, Armand Keating, Timothy Kieffer, Mohit Kapoor
83 585
Combining gene and mesenchymal stromal cell therapies: steps towards curing arthritis
Ostéoarthrite, ostéo-arthrite
Osteoarthritis (OA) is a debilitating disease characterized by progressive articular cartilage degeneration and is commonly followed by subchondral bone destruction and synovial inflammation. Globally, OA is the most common musculoskeletal disease, and more than three million Canadians have a reduced quality life because of it. With an aging population, there is a glaring need for safe and effective treatments for this debilitating chronic condition.
The current management of OA is mostly palliative and aimed at controlling pain and improving diseased joint function with physical therapy, while taking acetaminophen or non-steroidal systemic anti-inflammatories. Although these treatments reduce pain in some people, they do not cure the disease or prevent articular cartilage degeneration and disease progression. In an effort to reduce cartilage destruction in OA, some researchers have begun targeting inflammatory mediators, like (TNFα, IL-1B), that regulate the pain response as well as cartilage degeneration. Moreover, Mesenchymal Stromal Cells (MSCs), which can be isolated from various adult and neonatal tissues, and derivatives of pluripotent stem cells, have immunomodulatory properties that make them prime candidates for cell therapies to treat inflammatory diseases such as OA. An ongoing Health Canada approved phase I/II dose-escalation safety and efficacy study at the Toronto Western Hospital by members of this team is investigating the consequence of autologous injection of MSCs into the knee joints of patients with OA.
Here, we propose a novel approach by combining gene and cell therapy for the treatment of OA. We will harness mesenchymal stromal-like cells and chondrocytes, derived from pluripotent cells, to mediate an optimized anti-inflammatory response, while drug-inducibly delivering local-acting IL-1BRII, membrane-bound TGF-β1, a novel VEGF sticky-trap and TNFα sticky-trap biologics via transplanted cells to diseased joints. Prior to transplantation, the source of the therapeutic cells will be additionally modified to render them both non-tumorigenic (“Fail-Safe”) and immunologically tolerated (“cloaked”).
Our team combines decades of expertise in stem cell manipulation, the development of targeted biologics (Nagy), preclinical models to study and treat OA (Kapoor), MSC biology (Keating), and clinical use of MSCs to investigate novel disease treatments (Keating, Viswanathan). Combining gene and stem cell therapies is expected to increase the efficacy of treatment for this urgent clinical need. In cooperation with the CCRM, our approach is already on the path to commercialization and translation with the incorporation of a spin-off company (panCELLa Inc.), whose business plan is built on the clinical application of the “fail-safe” cell technology.
1 December 2016
31 December 2017
2016
Mohit Kapoor (C)
University Health Network
Équipes de recherche sur les maladies
Nagy
Cochercheur
Andras Nagy, Armand Keating, Timothy Kieffer, Mohit Kapoor
132 046
Combining gene and mesenchymal stromal cell therapies: steps towards curing arthritis
Ostéoarthrite, ostéo-arthrite
Osteoarthritis (OA) is a debilitating disease characterized by progressive articular cartilage degeneration and is commonly followed by subchondral bone destruction and synovial inflammation. Globally, OA is the most common musculoskeletal disease, and more than three million Canadians have a reduced quality life because of it. With an aging population, there is a glaring need for safe and effective treatments for this debilitating chronic condition.
The current management of OA is mostly palliative and aimed at controlling pain and improving diseased joint function with physical therapy, while taking acetaminophen or non-steroidal systemic anti-inflammatories. Although these treatments reduce pain in some people, they do not cure the disease or prevent articular cartilage degeneration and disease progression. In an effort to reduce cartilage destruction in OA, some researchers have begun targeting inflammatory mediators, like (TNFα, IL-1B), that regulate the pain response as well as cartilage degeneration. Moreover, Mesenchymal Stromal Cells (MSCs), which can be isolated from various adult and neonatal tissues, and derivatives of pluripotent stem cells, have immunomodulatory properties that make them prime candidates for cell therapies to treat inflammatory diseases such as OA. An ongoing Health Canada approved phase I/II dose-escalation safety and efficacy study at the Toronto Western Hospital by members of this team is investigating the consequence of autologous injection of MSCs into the knee joints of patients with OA.
Here, we propose a novel approach by combining gene and cell therapy for the treatment of OA. We will harness mesenchymal stromal-like cells and chondrocytes, derived from pluripotent cells, to mediate an optimized anti-inflammatory response, while drug-inducibly delivering local-acting IL-1BRII, membrane-bound TGF-β1, a novel VEGF sticky-trap and TNFα sticky-trap biologics via transplanted cells to diseased joints. Prior to transplantation, the source of the therapeutic cells will be additionally modified to render them both non-tumorigenic (“Fail-Safe”) and immunologically tolerated (“cloaked”).
Our team combines decades of expertise in stem cell manipulation, the development of targeted biologics (Nagy), preclinical models to study and treat OA (Kapoor), MSC biology (Keating), and clinical use of MSCs to investigate novel disease treatments (Keating, Viswanathan). Combining gene and stem cell therapies is expected to increase the efficacy of treatment for this urgent clinical need. In cooperation with the CCRM, our approach is already on the path to commercialization and translation with the incorporation of a spin-off company (panCELLa Inc.), whose business plan is built on the clinical application of the “fail-safe” cell technology.
1 December 2016
31 December 2017
2016
Andras Nagy (P)
Sinai Health System
Équipes de recherche sur les maladies
Nagy
Chercheur principal
Andras Nagy, Armand Keating, Timothy Kieffer, Mohit Kapoor
178 992
Combining gene and mesenchymal stromal cell therapies: steps towards curing arthritis
Osteoarthritis (OA) is a debilitating disease characterized by progressive articular cartilage degeneration and is commonly followed by subchondral bone destruction and synovial inflammation. Globally, OA is the most common musculoskeletal disease, and more than three million Canadians have a reduced quality life because of it. With an aging population, there is a glaring need for safe and effective treatments for this debilitating chronic condition.
The current management of OA is mostly palliative and aimed at controlling pain and improving diseased joint function with physical therapy, while taking acetaminophen or non-steroidal systemic anti-inflammatories. Although these treatments reduce pain in some people, they do not cure the disease or prevent articular cartilage degeneration and disease progression. In an effort to reduce cartilage destruction in OA, some researchers have begun targeting inflammatory mediators, like (TNFα, IL-1B), that regulate the pain response as well as cartilage degeneration. Moreover, Mesenchymal Stromal Cells (MSCs), which can be isolated from various adult and neonatal tissues, and derivatives of pluripotent stem cells, have immunomodulatory properties that make them prime candidates for cell therapies to treat inflammatory diseases such as OA. An ongoing Health Canada approved phase I/II dose-escalation safety and efficacy study at the Toronto Western Hospital by members of this team is investigating the consequence of autologous injection of MSCs into the knee joints of patients with OA.
Here, we propose a novel approach by combining gene and cell therapy for the treatment of OA. We will harness mesenchymal stromal-like cells and chondrocytes, derived from pluripotent cells, to mediate an optimized anti-inflammatory response, while drug-inducibly delivering local-acting IL-1BRII, membrane-bound TGF-β1, a novel VEGF sticky-trap and TNFα sticky-trap biologics via transplanted cells to diseased joints. Prior to transplantation, the source of the therapeutic cells will be additionally modified to render them both non-tumorigenic (“Fail-Safe”) and immunologically tolerated (“cloaked”).
Our team combines decades of expertise in stem cell manipulation, the development of targeted biologics (Nagy), preclinical models to study and treat OA (Kapoor), MSC biology (Keating), and clinical use of MSCs to investigate novel disease treatments (Keating, Viswanathan). Combining gene and stem cell therapies is expected to increase the efficacy of treatment for this urgent clinical need. In cooperation with the CCRM, our approach is already on the path to commercialization and translation with the incorporation of a spin-off company (panCELLa Inc.), whose business plan is built on the clinical application of the “fail-safe” cell technology.
1 December 2016
31 December 2017
2016
Gregory Korbutt (C)
University of Alberta
Équipes de recherche sur les maladies
Shapiro
Cochercheur
James Shapiro, Gregory Korbutt
244 905
Development of a novel stem cell-derived transplant modality for type 1 diabetes
Diabète
Islet transplantation has demonstrated that the replacement of insulin-producing β-cells is an effective means of restoring blood glucose control in patients with type 1 diabetes (T1D), especially in subjects at risk of severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors must be addressed. Remarkable progress has occurred in stem cell technology regarding clinical-grade insulin-producing cells with the capacity for limitless expansion; solving inadequate organ donor supply. Our group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s (world leader in stem cell development) VC-01 and VC-02 combination products in a cohort of patients with T1D in Edmonton. This trial examines the ability of ViaCyte’s insulin-producing pancreatic endoderm cells (PEC) to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into National and Worldwide clinical practice. The objective of this SCN proposal is to use an innovative approach to bioengineer a retrievable, functionalized scaffold, that houses and supports long-term function of ViaCyte’s PEC cells to treat T1D. The Disease Team consists of Dr. James Shapiro and Dr. Gregory Korbutt. As a clinical scientist and Director of the Clinical Islet Transplant Program, Dr. Shapiro is internationally recognized for his pioneering contributions to the development of the ‘Edmonton Protocol’, and is currently leading thirteen clinical trials in islet, stem cell and liver transplantation. Co-PI, Dr. Korbutt, is the Scientific Director of the cGMP “Alberta Cell Therapy Manufacturing Facility” for cell and tissue production, with significant expertise in islet biology and transplantation. The Team has also established a productive collaboration the Ingenuity Lab Nanotechnology Accelerator, with Dr. Puru Kuppan, a multidisciplinary R&D initiative focused on groundbreaking nanotechnology advances. Strategies for further commercialization will be conducted with support from TEC Edmonton, whom has provided support in filing US and Canadian provisional patents for this technology. This research proposal has been developed by a group of investigators offering unique expertise in clinical islet transplantation and stem cell biology, as well as biomaterial engineering expertise. With an active clinical islet transplant program in Edmonton, a new cGMP facility for the clinical grade production of cells, and the bioactive scaffold design expertise of the Ingenuity’s Laboratory, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 December 2016
31 December 2017
2016
James Shapiro (P)
University of Alberta
Équipes de recherche sur les maladies
Shapiro
Chercheur principal
James Shapiro, Gregory Korbutt
252 000
Development of a novel stem cell-derived transplant modality for type 1 diabetes
Diabète
Islet transplantation has demonstrated that the replacement of insulin-producing β-cells is an effective means of restoring blood glucose control in patients with type 1 diabetes (T1D), especially in subjects at risk of severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors must be addressed. Remarkable progress has occurred in stem cell technology regarding clinical-grade insulin-producing cells with the capacity for limitless expansion; solving inadequate organ donor supply. Our group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s (world leader in stem cell development) VC-01 and VC-02 combination products in a cohort of patients with T1D in Edmonton. This trial examines the ability of ViaCyte’s insulin-producing pancreatic endoderm cells (PEC) to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into National and Worldwide clinical practice. The objective of this SCN proposal is to use an innovative approach to bioengineer a retrievable, functionalized scaffold, that houses and supports long-term function of ViaCyte’s PEC cells to treat T1D. The Disease Team consists of Dr. James Shapiro and Dr. Gregory Korbutt. As a clinical scientist and Director of the Clinical Islet Transplant Program, Dr. Shapiro is internationally recognized for his pioneering contributions to the development of the ‘Edmonton Protocol’, and is currently leading thirteen clinical trials in islet, stem cell and liver transplantation. Co-PI, Dr. Korbutt, is the Scientific Director of the cGMP “Alberta Cell Therapy Manufacturing Facility” for cell and tissue production, with significant expertise in islet biology and transplantation. The Team has also established a productive collaboration the Ingenuity Lab Nanotechnology Accelerator, with Dr. Puru Kuppan, a multidisciplinary R&D initiative focused on groundbreaking nanotechnology advances. Strategies for further commercialization will be conducted with support from TEC Edmonton, whom has provided support in filing US and Canadian provisional patents for this technology. This research proposal has been developed by a group of investigators offering unique expertise in clinical islet transplantation and stem cell biology, as well as biomaterial engineering expertise. With an active clinical islet transplant program in Edmonton, a new cGMP facility for the clinical grade production of cells, and the bioactive scaffold design expertise of the Ingenuity’s Laboratory, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 December 2016
31 December 2017
2016
Vahab Soleimani (P)
Jewish General Hospital
Équipes de recherche sur les maladies
Soleimani
Chercheur principal
Vahab Soleimani
200 000
Interfering niche-related reprogramming of stem cells during aging
Muscle, muscles
Adult stem cells are indispensable for tissue homeostasis and repair. In the musculoskeletal system (i.e. skeletal muscle, bone and connective tissue), there is a severe age-related decline in stem cell functionality and tissue repair. This functional decline of stem cells leads to degenerative diseases such as osteoporosis and sarcopenia in the elderly population. Recent experimental evidence suggests that age-related defect in tissue repair could be reversed. However, the molecular mechanisms underlying the plasticity and reversibility of tissue repair in degenerative diseases such as sarcopenia and osteoporosis remains a challenge. Multiple lines of evidence suggest that epigenetic alterations play key roles in the aging process, as cells from aged individuals exhibit reduced area of heterochromatin and loss of repressive histone marks. The reversibility of epigenetic mechanisms by various drugs provides great opportunities to develop urgently needed therapies for many debilitating diseases including the age-related musculoskeletal disorders. However, there is a knowledge gap on how stem cell functionality is lost in degenerative disorders and how aging in general impacts stem cell function and tissue repair. Adult stem cells reside within a defined anatomical location called “the niche” where the stem cell constantly communicates with the surrounding environment and with the neighbouring cells. In patients with degenerative diseases and during aging the environment surrounding the stem cells changes with regards to the cellular content and the chemical signals. Consequently, in the diseased conditions stem cells lose their ability to maintain tissue repair. In this project we aim to determine how changes in the stem cell niche during aging impairs tissue regeneration using hematopoietic, mesenchymal and skeletal muscle stem cells. We hypothesize that the diseased niche alters gene expression profile by modifying the stem cell epigenome. Therefore, we will perform allogeneic stem cell transplantation between young and old mice and map the transcriptional and epigenetic changes that take place as a result of changing niche environment. Using stem cells from three distinct lineages will identify conserved genetic networks that are altered with age. Importantly, by doing reciprocal stem cell transplantation from young to old and vice versa we will determine the “reversible” genetic networks that can be targeted in degenerative musculoskeletal diseases. Finally, we will validate the results in human cells and tissue biopsies to assess the translational potentials. The long-term goal of this project is to develop novel stem cell-based therapies to boost tissue regeneration for musculoskeletal degenerative disorders.
1 December 2016
31 December 2017
2016
Massimiliano Paganelli (P)
CHU Sainte-Justine
Équipes de recherche sur les maladies
Paganelli
Chercheur principal
Massimiliano Paganelli
199 982
Treatment of chronic liver failure by stem cell-derived mature liver tissue
Insuffisance hépatique
One in ten Canadians is affected by liver disease. The standard of care for liver failure (the common outcome of any progressive liver disease) is liver transplantation, but only 400 transplants are performed each year in Canada for over 5000 liver deaths/year. Thus, there is an urgent need for new therapies capable of replacing liver functions in children and adults with cirrhosis and liver failure. The final aim of this multidisciplinary project is to develop and test an innovative stem cell-based product to restore the lacking liver functions in such patients, improving survival and preventing/treating complications. Our team is composed of a transplant hepatologist expert in stem cell therapy (Dr. Paganelli, CHU Sainte-Justine), two leaders in the field of biomaterials (Dr. Shikanov at University of Michigan, and Dr. Ma, Cornell University), and a molecular oncologist expert in pre-clinical studies (Dr. Petrocca, Boston University). Using our clinical-grade human stem cells we are able to generate 3D cellular microaggregates (organoids) expressing the functions of a healthy liver. We will embed such organoids in a Health Canada-approved synthetic hydrogel we previously developed. Such a biomaterial supports the survival and maturation of the embedded organoids, allowing them to exchange nutrients and substances with the environment and providing complete isolation from the immune system upon implantation into a recipient. Upon encapsulation into this semi-solid hydrogel, our organoids will express most of the functions of a mature liver tissue. Once implanted into a patient with liver failure, such an encapsulated mature liver tissue (EMLT) will be able to purify the patient’ blood from toxic substances and synthesize proteins needed for vital functions, improving survival and preventing severe complications, without the risk of rejection (thus eliminating the need for lifelong immunosuppression). If successful, such a pioneering approach will allow using a single stem cell population to manufacture an off-the-shelf, sustainable product to potentially treat thousands of people. We will conduct thorough pre-clinical studies assessing the efficacy and the short- and long-term safety of this product, in compliance with Health Canada requirements, in order to prepare for an early-phase clinical trial in the medium term (5 years). In collaboration our partners, the EMLT will be patented and options for its commercialization through a spin-off company creation or out-licensing to biopharmaceuticals companies will be explored. If successful, this project will deliver an innovative product to treat liver failure, with the potential of saving hundreds of thousands of patients worldwide.
1 December 2016
31 December 2017
2016
Amy Zarzeczny (C)
University of Regina
Recherche d’impact, politique publique
Caulfield
Cochercheur
Timothy Caulfield, Amy Zarzeczny
5 000
Stem cells and misleading marketing claims
QEJS, questions éthiques, juridiques et sociales
The development of health technologies traditionally follows a linear path from discovery through clinical research and, when successful, market approval. In the stem cell arena, however, the path is more multi-pronged than linear, and incorporates different points of access to interventions outside of clinical trials. This is a complex landscape that is especially important for stem cell procedures for as-yet unapproved medical reasons, also known as off-label use. In this study, we are specifically interested in the case of multiple sclerosis (MS) for which, following significant clinical trials activity, patients may be faced with decisions about off-label stem cell transplants. To narrow the gap in this understudied domain of off-label interventions, we will interview MS patients and explore with them the evaluative criteria and decision-making processes that lead them to an off-label bone marrow stem cell transplant over the more conventional alternatives of participating in a clinical trial or waiting for a market-approved therapy. We will deliver the knowledge we gain and its products in the form of evidence-informed resources and recommendations to patients and providers to elevate “informed” in the equation of “informed choices” about investigational stem cell products in the face of chronic, neurodegenerative disease.
1 December 2016
31 December 2017
2016
Timothy Caulfield (P)
University of Alberta
Recherche d’impact, politique publique
Caulfield
Chercheur principal
Timothy Caulfield, Amy Zarzeczny
45 000
Stem cells and misleading marketing claims
QEJS, questions éthiques, juridiques et sociales
The development of health technologies traditionally follows a linear path from discovery through clinical research and, when successful, market approval. In the stem cell arena, however, the path is more multi-pronged than linear, and incorporates different points of access to interventions outside of clinical trials. This is a complex landscape that is especially important for stem cell procedures for as-yet unapproved medical reasons, also known as off-label use. In this study, we are specifically interested in the case of multiple sclerosis (MS) for which, following significant clinical trials activity, patients may be faced with decisions about off-label stem cell transplants. To narrow the gap in this understudied domain of off-label interventions, we will interview MS patients and explore with them the evaluative criteria and decision-making processes that lead them to an off-label bone marrow stem cell transplant over the more conventional alternatives of participating in a clinical trial or waiting for a market-approved therapy. We will deliver the knowledge we gain and its products in the form of evidence-informed resources and recommendations to patients and providers to elevate “informed” in the equation of “informed choices” about investigational stem cell products in the face of chronic, neurodegenerative disease.
1 December 2016
31 December 2017
2016
Judy Illes (P)
University of British Columbia
Recherche d’impact, politique publique
Illes
Chercheur principal
Judy Illes
50 000
Decision-making in translation: ugency, access, and evaluation in off-label stem cell interventions
QEJS, questions éthiques, juridiques et sociales
The development of health technologies traditionally follows a linear path from discovery through clinical research and, when successful, market approval. In the stem cell arena, however, the path is more multi-pronged than linear, and incorporates different points of access to interventions outside of clinical trials. This is a complex landscape that is especially important for stem cell procedures for as-yet unapproved medical reasons, also known as off-label use. In this study, we are specifically interested in the case of multiple sclerosis (MS) for which, following significant clinical trials activity, patients may be faced with decisions about off-label stem cell transplants. To narrow the gap in this understudied domain of off-label interventions, we will interview MS patients and explore with them the evaluative criteria and decision-making processes that lead them to an off-label bone marrow stem cell transplant over the more conventional alternatives of participating in a clinical trial or waiting for a market-approved therapy. We will deliver the knowledge we gain and its products in the form of evidence-informed resources and recommendations to patients and providers to elevate “informed” in the equation of “informed choices” about investigational stem cell products in the face of chronic, neurodegenerative disease.
1 December 2016
31 December 2017
2016
Amy Zarzeczny (C)
University of Regina
Recherche d’impact, politique publique
Ogbogu
Cochercheur
Ubaka Ogbogu, Amy Zarzeczny
10 000
Regulating the future: model policies for emerging stem cell research activities, including research on gene-edited and reconstituted embryos
QEJS, questions éthiques, juridiques et sociales
The development of health technologies traditionally follows a linear path from discovery through clinical research and, when successful, market approval. In the stem cell arena, however, the path is more multi-pronged than linear, and incorporates different points of access to interventions outside of clinical trials. This is a complex landscape that is especially important for stem cell procedures for as-yet unapproved medical reasons, also known as off-label use. In this study, we are specifically interested in the case of multiple sclerosis (MS) for which, following significant clinical trials activity, patients may be faced with decisions about off-label stem cell transplants. To narrow the gap in this understudied domain of off-label interventions, we will interview MS patients and explore with them the evaluative criteria and decision-making processes that lead them to an off-label bone marrow stem cell transplant over the more conventional alternatives of participating in a clinical trial or waiting for a market-approved therapy. We will deliver the knowledge we gain and its products in the form of evidence-informed resources and recommendations to patients and providers to elevate “informed” in the equation of “informed choices” about investigational stem cell products in the face of chronic, neurodegenerative disease.
1 December 2016
31 December 2017
2016
Ubaka Ogbogu (P)
University of Alberta
Recherche d’impact, politique publique
Ogbogu
Chercheur principal
Ubaka Ogbogu, Amy Zarzeczny
40 000
Regulating the future: model policies for emerging stem cell research activities, including research on gene-edited and reconstituted embryos
QEJS, questions éthiques, juridiques et sociales
The development of health technologies traditionally follows a linear path from discovery through clinical research and, when successful, market approval. In the stem cell arena, however, the path is more multi-pronged than linear, and incorporates different points of access to interventions outside of clinical trials. This is a complex landscape that is especially important for stem cell procedures for as-yet unapproved medical reasons, also known as off-label use. In this study, we are specifically interested in the case of multiple sclerosis (MS) for which, following significant clinical trials activity, patients may be faced with decisions about off-label stem cell transplants. To narrow the gap in this understudied domain of off-label interventions, we will interview MS patients and explore with them the evaluative criteria and decision-making processes that lead them to an off-label bone marrow stem cell transplant over the more conventional alternatives of participating in a clinical trial or waiting for a market-approved therapy. We will deliver the knowledge we gain and its products in the form of evidence-informed resources and recommendations to patients and providers to elevate “informed” in the equation of “informed choices” about investigational stem cell products in the face of chronic, neurodegenerative disease.
1 December 2016
31 December 2017
2018
Jean Roy (P)
Hôpital Maisonneuve-Rosemont
Subventions de soutien des essais cliniques
Roy
Chercheur principal
Jean Roy
500 000
Allogeneic stem cell transplant using UM171 expanded cord bloods for patients with high-risk multiple myeloma
Sang, myélome
Multiple myeloma, the second most common blood cancer in Canada, remains incurable with a life expectancy of 5-6 years. Myeloma patients with advanced disease, chromosome abnormalities, myeloma cells in the blood or who are unresponsive to initial therapy have an even worse survival of approximately 3 years. To date, the only curative option for multiple myeloma is an allogeneic stem cell transplant (a transplant from a family or unrelated donor). However, allogeneic transplant is associated with serious side effects, the most significant being the donor cells attacking various recipient’s organs, a condition called graft-versus-host disease, leading to an early mortality of 10-20%. In patients who survive, long-term immune complications (80%) and relapse (50%) remain frequent. Clearly, allogeneic transplant needs to be improved in order to cure more patients.
In this study, we propose to use the unique properties of cord blood in order to make allogeneic transplant safer and more successful for myeloma patients. Cord blood use is associated with a much lower incidence of immune complications while having strong anti-cancer activity. It has been used for decades in children, less so in adults due to small number of stem cells in the graft leading to slow blood counts recovery after transplant. Recently, a novel molecule discovered by Canadian scientists in Montreal, UM171, has been shown to increase the number of stem cells and anti-cancer immune cells in laboratory, with promising results in the first 17 adults transplanted. In this study, cord bloods will be cultured in laboratory then infused in 10 patients with myeloma at higher risk of relapse. We expect a decreased incidence of immune complications and lower incidence of relapse. If successful, allogeneic transplant using cord bloods expanded with UM171 could become the treatment of choice for patients with poor prognosis multiple myeloma in the near future.
1 April 2018
28 February 2019
2018
James Shapiro (P)
University of Alberta
Subventions de soutien des essais cliniques
Shapiro
Chercheur principal
James Shapiro
500 000
Pancreatic Progenitor Cell Therapy: Solving Supply and Survival Issues of Islet Cell Transplantation for T1DM
Diabète
The proposed project is aimed at treating, and functionally curing, type 1 diabetes mellitus (T1D) patients with embryonic stem cell-derived islet replacement therapy. There is no known way to prevent or cure T1D. Since the primary pathogenesis of T1D is the loss of the insulin-producing beta cells in the pancreas, it is a good candidate for cell replacement therapy. Cadaver islet transplantation represents clinical proof-of-concept for this approach, and the pluripotent stem cell-based technologies have the potential to solve the current shortage of material, as well as to provide reliable, high quality implantable material delivered in a safe and broadly applicable format.
The VC01 trial is designed to target all insulin-utilizing patients, including at least 270,000 Canadians and 40 million worldwide; the VC02 trial targets 10% T1D patients at high risk of acute complications. Both use the same pancreatic endoderm cells (PEC-01). These patients suffer insulin injection, hypoglycemia unawareness, and severe hypoglycemic episodes, which can be sometimes fatal. Medical care costs for people with diabetes are more than two times higher than for those without diabetes.
ViaCyte has made great progress in developing a practical islet cell replacement therapy, and the Edmonton Team has collaborated with them both in pre-clinical and clinical studies previously (VC01 cohort 1 and VC02 cohort 1 – SCN funded). The proposal herein is to perform clinical testing of an improved VC01 delivery device to demonstrate clinically relevant efficacy, and the VC02 in high-risk T1D patients (cohort 2) to assess safety and efficacy.
The project is likely the most expedient way to assess this therapy in T1D patients with the most urgent unmet medical need. VC01/VC02 products could transform and save the lives of countless people suffering with T1D, and eventually minimize the resource stress placed on our healthcare system.
1 April 2018
28 February 2019
2018
Duncan Stewart (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien des essais cliniques
Stewart
Chercheur principal
Duncan Stewart
500 000
ENhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT- AMI)
Cardiaque
Rationale: Patients with a large area of damaged heart muscle after a heart attack have a high risk for heart failure and death. Cell-based gene therapy could restore working muscle in regions that otherwise would form only scar tissue, and lead to better heart repair and function.
Purpose: The primary objectives of the ENACT-AMI trial are to determine whether the administration of a patient’s own (autologous) Endothelial Progenitor Cells (EPCs) is safe and effective in improving cardiac function following large heart attack, and whether the use of cells that are genetically engineered by adding extra copies of a gene that is critical for blood vessel function and repair, namely endothelial Nitric Oxide Synthase (eNOS), is superior to non-modified cells. A secondary objective is to determine whether the benefit of EPC therapy depends on the timing of cell delivery (5-15 days versus 16-30 days post-STEMI).
Novel aspects: The use of the patient’s own cells avoids the immunological rejection that occurs with transplantation of cells from other individuals, but is greatly hampered by the fact that the reparative activities of stem and progenitor cells are negatively influenced by the host risk factors that lead to heart disease in the first place, namely advanced age, high cholesterol, diabetes and so forth. We have shown that adding extra copies of the eNOS gene (which protects blood vessels and promotes their growth and repair) can restore the activity of EPCs from heart patients by almost 90%. ENACT-AMI is the first clinical trial in the world to include a strategy designed to enhance the function of a patient’s own cells, and the first to use combination gene and cell therapy, for the treatment of heart disease.
Benefits to Canadians and Canada: While outcomes after heart attacks have greatly improved with the advent of modern therapies to open up the blocked coronary artery (reperfusion therapy), about 20% of patients fail to receive the expected benefits of reperfusion therapy, and face the consequences of large heart damage and subsequent heart failure. Should gene-enhanced EPCs provide an effective adjunctive treatment for these patients, this would avoid a high individual burden of chronic debilitating disease, while reducing the high costs to the health care system which in Canada totals $2.8 billion per year for heart failure (heartandstroke.ca/heartreport). If successful, ENACT investigators are well positioned to disseminate such a therapy across Canada though CellCAN, a unique network of cell manufacturing facilities across Canada.
1 April 2018
28 February 2019
2018
Timothy Kieffer (P)
University of British Columbia
Recherche d’impact, clinical translation et accelerator
Kieffer
Chercheur principal
Timothy Kieffer
100 000
Assessment of Cell Maturation and Function in Subcutaneous Macroencapsulation Devices in Rodents
Diabète
Diabetes is a disease caused by insufficient production of the hormone insulin, resulting in elevated blood sugar levels and damage to several tissues leading to debilitating complications. As a result, many patients with diabetes face a daily routine of insulin injections and careful monitoring of blood sugar levels. Our overall goal is to develop a cell-based therapy for diabetes, given the successful treatment of diabetes with insulin producing islet cells that are isolated from the pancreas of organ donors. We believe we can eliminate the reliance on organ donors by the transplant of differentiated stem cells, whereby the cells take over the automatic production of insulin and control of blood sugar levels. We have developed cell culture procedures to generate large quantities of insulin-producing cells that can reverse diabetes in rodents. With support from JDRF and ViaCyte, we are examining the success of this approach when transplanting the cells under the skin. We now plan to extend these studies to test the effectiveness of two different devices that are currently being used in clinical trials. Both devices are designed to be implanted under the skin and contain the cells, but one design includes small holes that are intended to improve the blood supply to the cells within the device. We plan to investigate how these two different devices function when stem cells are differentiated either to pancreatic precursor cells, mimicking the current clinical trials, or beyond to mature insulin producing cells prior to implant. Moreover, we plan to assess the devices in both mice and rats, to determine which model may better predict the clinical outcome. Finally, we will assess both devices with isolated human islets. Collectively, these studies will support ongoing clinical testing in patients with diabetes that ultimately aim to eliminate the need for insulin administration by needle.
1 April 2018
28 February 2019
2018
Zachary Laksman (P)
University of British Columbia
Recherche d’impact, clinical translation et accelerator
Laksman
Chercheur principal
Zachary Laksman
Glen Tibbits
90 000
High throughput novel drug screening in human tissue model of atrial fibrillation
Maladie du cœur, maladies du cœur, maladie cardiaque, maladies cardiaques
Stem cells are an important and effective tool in cardiac research and drug screening and have demonstrated the ability to model human disease, and predict the safety and effectiveness of drugs. The need for this technology in drug testing is particularly pressing given that 9 out of 10 new compounds fail after moving from the research labs to human studies. Most concerning is the fact that 1 out of 3 of these drugs is found to have toxic effects, with the majority causing serious side effects that affect the heart. The most feared consequence of heart toxicity is a dangerous heart rhythm that can lead to sudden death. Because of this growing concern, the FDA has mandated that all new compounds be screened for this specific heart toxicity, however the current model systems are extremely poor at doing so. Heart cells derived from stem cells carry all of the critical electrical machinery, and thus are the best-suited model for testing drug toxicity before human trials. Equally important to drug safety is the identification of novel compounds that have the best chance of being effective, prior to proceeding to expensive clinical trials. For many diseases, there remain few safe and effective options, and significant barriers when moving from preliminary excitement to clinical utility. The weakness remains here too in the model system with which drugs are studied. Atrial Fibrillation, a heart rhythm disorder, is perhaps one of the best examples as it is extremely common, has a significant impact on individual health and on society, and yet the current drug treatment options are ineffective and often unsafe. It is for this reason that our group generated the world’s first stem cell model of atrial fibrillation. We propose to modify our model in order to quickly screen a large number of novel compounds at various stages of development in order to determine whether or not they would be safe and effective for patients with atrial fibrillation.
1 April 2018
28 February 2019
2018
Glen Tibbits (C)
Simon Fraser University
Recherche d’impact, clinical translation et accelerator
Laksman
Cochercheur
Zachary Laksman
Glen Tibbits
10 000
High throughput novel drug screening in human tissue model of atrial fibrillation
Maladie du cœur, maladies du cœur, maladie cardiaque, maladies cardiaques
Stem cells are an important and effective tool in cardiac research and drug screening and have demonstrated the ability to model human disease, and predict the safety and effectiveness of drugs. The need for this technology in drug testing is particularly pressing given that 9 out of 10 new compounds fail after moving from the research labs to human studies. Most concerning is the fact that 1 out of 3 of these drugs is found to have toxic effects, with the majority causing serious side effects that affect the heart. The most feared consequence of heart toxicity is a dangerous heart rhythm that can lead to sudden death. Because of this growing concern, the FDA has mandated that all new compounds be screened for this specific heart toxicity, however the current model systems are extremely poor at doing so. Heart cells derived from stem cells carry all of the critical electrical machinery, and thus are the best-suited model for testing drug toxicity before human trials. Equally important to drug safety is the identification of novel compounds that have the best chance of being effective, prior to proceeding to expensive clinical trials. For many diseases, there remain few safe and effective options, and significant barriers when moving from preliminary excitement to clinical utility. The weakness remains here too in the model system with which drugs are studied. Atrial Fibrillation, a heart rhythm disorder, is perhaps one of the best examples as it is extremely common, has a significant impact on individual health and on society, and yet the current drug treatment options are ineffective and often unsafe. It is for this reason that our group generated the world’s first stem cell model of atrial fibrillation. We propose to modify our model in order to quickly screen a large number of novel compounds at various stages of development in order to determine whether or not they would be safe and effective for patients with atrial fibrillation.
1 April 2018
28 February 2019
2018
Lauralyn McIntyre (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Recherche d’impact, clinical translation et accelerator
McIntyre
Chercheur principal
Lauralyn McIntyre
100 000
Cellular Immunotherapy for Septic Shock (CISS2): A Phase II Multicentre Clinical Trial
Septicémie
Cellular Immunotherapy for Septic Shock (CISS): A Phase II Multicentre Clinical Trial
1 April 2018
28 February 2019
2018
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Recherche d’impact, clinical translation et accelerator
Thébaud
Chercheur principal
Bernard Thébaud
99 905
Endothelial Progenitor Cell-derived Therapies for Neonatal Pulmonary Hypertension
Maladie pulmonaire, maladies pulmonaires, maladie des poumons, maladies des poumons
High blood pressure in the lungs (pulmonary hypertension, PH) complicates lung diseases in babies with overly small lungs. PH doubles the risk of death, and survivors have long-term health problems. Today, there is no treatment to make small lungs grow bigger or lower the PH. Our lab was the first to show that endothelial progenitor cells (EPCs) can make new blood vessels in the lung, and thus make the lung grow and lower PH. EPCs may replace diseased endothelial cells in the lung; but EPCs more likely produce tiny particles (exosomes) that contain healing factors in the right amount and at the right time so that new blood vessels can grow. These cells can be seen as “smart local pharmacies” that control appropriate blood vessel growth. We are using induced pluripotent-derived (i)EPCs produced by our long-term collaborator Dr. Mervin Yoder, because these cells can be easily produced in very high quantities, and because these cells are younger and healthier than those from adult patients. We will test if these iEPCs or exosomes are safe and effective in experimental neonatal PH. If so, our research will bring a breakthrough treatment for PH and save lives and/or improve the quality of life of patients. Our discovery may also benefit other Canadians and patients around the world that suffer from diseases with low blood supply such as heart attack, stroke or preeclampsia (high blood pressure in pregnant women that can put the life of both mother and baby at risk; it often requires a C-section and preterm delivery of the baby). This new cell product has potential for commercialization and has already led our partner Dr. Mervin Yoder to create a spin-off company (Vascugen) enabling the development and clinical translation of a clinical-grade cell product that can be used in humans.
1 April 2018
28 February 2019
2018
Glen Tibbits (P)
Simon Fraser University
Recherche d’impact, clinical translation et accelerator
Tibbits
Chercheur principal
Glen Tibbits
99 500
Developing an hiPSC-CM based protocol to investigate SIDS-implicated sudden cardiac arrest in infants
Cardiaque
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 April 2018
28 February 2019
2018
Xudong Cao (C)
Université d’Ottawa
Recherche d’impact, clinical translation et accelerator
Tsai
Cochercheur
Xudong Cao, Eve Tsai
28 915
Translating an animal endogenous stem/progenitor cell repair strategy for stroke to humans
Affecting fifteen thousand Canadians per annum, current treatment options for stroke are limited and cannot repair brain damage and loss of function. The stimulation of the brain’s own stem cells, called endogenous neural stem/progenitor cells (eNSPCs) has been extensively studied in cell culture and animal models as a promising therapy which allows the brain to repair and restore neurological function after damage. Several animal studies demonstrate that growth factors can significantly increase the number of eNSPCs and restore motor function in animal models of stroke. The targeted release of growth factors presents a challenge as the current mode of delivery, intraventricular infusion, is invasive and cannot be easily applied to human patients, rendering this promising therapy “clinically impractical”.
To overcome this clinical impracticality, we purpose to develop a novel and clinically applicable regeneration factor-releasing biomaterial that can stimulate and promote functional recovery after stroke. The biomaterial would be applied as part of decompressive craniectomy (DC): a routine surgical procedure performed on stroke patients with malignant middle cerebral artery infarction. This biomaterial will facilitate the combined delivery of three promising regeneration factors, epidermal growth factor (EGF), fibroblast growth factor-2 (FGF2) and erythropoietin (EPO), all of which have proven to be effective as a combination therapy in animal models, in order to translate this promising therapy to human patients.
Our preliminary results have shown that this novel biomaterial is able to stimulate and sustain the growth of primary neural stem cells in vitro. Our next step is to evaluate the efficacy of this novel biomaterial in the regeneration of neural tissue and functional recovery in vivo using a rat middle cerebral artery occlusion (MCAO) model. This proof of principle project will allow us to perform the necessary preclinical and pilot studies in order to translate this therapy for clinical application.
1 April 2018
28 February 2019
2018
Eve Tsai (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Recherche d’impact, clinical translation et accelerator
Tsai
Chercheur principal
Xudong Cao, Eve Tsai
71 085
Translating an animal endogenous stem/progenitor cell repair strategy for stroke to humans
Affecting fifteen thousand Canadians per annum, current treatment options for stroke are limited and cannot repair brain damage and loss of function. The stimulation of the brain’s own stem cells, called endogenous neural stem/progenitor cells (eNSPCs) has been extensively studied in cell culture and animal models as a promising therapy which allows the brain to repair and restore neurological function after damage. Several animal studies demonstrate that growth factors can significantly increase the number of eNSPCs and restore motor function in animal models of stroke. The targeted release of growth factors presents a challenge as the current mode of delivery, intraventricular infusion, is invasive and cannot be easily applied to human patients, rendering this promising therapy “clinically impractical”.
To overcome this clinical impracticality, we purpose to develop a novel and clinically applicable regeneration factor-releasing biomaterial that can stimulate and promote functional recovery after stroke. The biomaterial would be applied as part of decompressive craniectomy (DC): a routine surgical procedure performed on stroke patients with malignant middle cerebral artery infarction. This biomaterial will facilitate the combined delivery of three promising regeneration factors, epidermal growth factor (EGF), fibroblast growth factor-2 (FGF2) and erythropoietin (EPO), all of which have proven to be effective as a combination therapy in animal models, in order to translate this promising therapy to human patients.
Our preliminary results have shown that this novel biomaterial is able to stimulate and sustain the growth of primary neural stem cells in vitro. Our next step is to evaluate the efficacy of this novel biomaterial in the regeneration of neural tissue and functional recovery in vivo using a rat middle cerebral artery occlusion (MCAO) model. This proof of principle project will allow us to perform the necessary preclinical and pilot studies in order to translate this therapy for clinical application.
1 April 2018
28 February 2019
2018
Derrick Rancourt (P)
University of Calgary
Recherche d’impact, commercialisation
Rancourt
Chercheur principal
Derrick Rancourt
100 000
Enhancing the Efficiency of Genome Engineering in Human Pluripotent Stem Cells
Ingénierie génomique
Genome engineering (GE) can allow the correction of disease genes in patient-derived pluripotent stem cells (PSCs), which in turn can be used for regenerative medicine/gene therapy purposes. While straightforward in mouse (m) PSCs, it is very challenging in human (h) PSCs. For the gene transfer that is required for GE, cells need to be enzymatically dissociated. hPSCs are prone to anoikis, a form of cell death that occurs when cells are dissociated. Although the rho kinase inhibitor, Y-27632, suppresses anoikis and, in turn, allows some transfection to occur, it is rather inefficient, making it difficult to generate enough clones to screen for engineered mutations. As an alternative approach, we have recently identified a small molecule, which substantially improves hPSC gene transfer efficiency when combined with Y-27632. By investigating mechanism, in partnership with Stemcell Technologies Inc. (STI), we will further improve the efficiency of hPSC gene transfer. After optimizing efficiency, we will demonstrate that our technology also increases the efficiency of hPSC GE. After successful demonstration of both, we will license the technology to STI for commercialization.
1 April 2018
28 February 2019
2018
Peter Zandstra (P)
University of British Columbia
Recherche d’impact, commercialisation
Zandstra
Chercheur principal
Peter Zandstra
100 000
A robust, quantitative, and high-throughput assay to rapidly characterize human induced pluripotent stem cells.
Caractérisation des CSPi
Regenerative medicine has witnessed a dramatic upsurge in the establishment of human induced pluripotent stem cell (hiPSC) lines for cell therapy and disease modelling applications1–3. Although pluripotent (able to specify to any somatic cell), the efficiencies with which hiPSC lines differentiate into specific lineages dramatically vary between lines4–7. This underscores the need for assays that characterize hiPSC differentiation capacity to enable rapid clinical translation.
Recent evidence has demonstrated the remarkable ability of stem cells to organize into structures that closely mimic developmental events8,9. We recently capitalized on this capability of stem cells and using a novel high-throughput micropatterning platform, identified defined conditions that model human gastrulation10 – a stage during embryogenesis when the pluripotent stem cells segregate into the three germ layers11–13. Furthermore, we employed a readily accessible image analysis pipeline to enable rigorous and quantitative analyses of the high-content immunofluorescence data generated by our platform10. Our platform is of high value to the field of regenerative medicine as it can be utilized as a valuable assay to characterize differentiation propensity of the large numbers of hiPSC lines being currently generated.
We propose establishing our technology as a rapid, quantitative, and inexpensive assay tailored toward hiPSC characterization. To this end, we will collaborate with the Human Induced Pluripotent Stem Cell Initiative (HipSci) – a world leading consortium with over 700 thoroughly characterized hiPSC lines14. This partnership represents a valuable opportunity as it provides us the platform for the rigorous establishment of our assay. Furthermore, our commercial partnership with StemCell will allow us to manufacture and distribute the technology, and obtain protection for novel intellectual property. Canadians will be benefited in the short term via job creation and tax revenue, and in the longer term by contributing to a dominant Canadian position in regenerative medicine.
Untreatable retinal degeneration dramatically affects millions of people, both young and old. In Canada, vision loss incurs the highest direct healthcare costs of any disease group – $33,000/patient/year. Globally, age-related macular degeneration (AMD) has an economic cost of over $350 billon (USD) annually, let alone the many other diseases that cause untreatable retinal degeneration.
Fortunately, stem-cell-based therapeutics are rapidly approaching the level of efficacy, safety, and economic scalability needed for clinical adoption. However, a central barrier remains for vision to be restored to the vast majority of patients that suffer from advanced retinal degeneration, that both the retinal pigment epithelium (RPE) and photoreceptor (PR) layers – co-dependant layers – must be regenerated. Unfortunately, these graft cells have not been shown to self-stratify and thus cannot be simply co-injected. Current best graft delivery efforts use scaffolds or sheets, which often do more harm than good or provide negligible coverage.
We have developed a cell-based therapeutic that addresses this translational roadblock by non-invasively inducing (via proprietary technology) dual-graft (RPE+PR) suspension injected into the subretinal space into polarized – stratified – layers with extensive fundus-coverage. This is achieved using standard clinical techniques and infrastructure, which reduces costs and increases likelihood of clinical adoption. We have attained dual-graft stratification in live rabbit trials. Despite these promising graft-architecture data, further optimization through larger-scale animal trials is required to obtain the efficacy and safety data to attract the considerable investment and partnerships needed to initiate clinical trials in Canada. Our core aims are: 1) generating dual-graft stratification in clinically relevant: graft (stem-cell-derived) and hosts (rabbits that have lost their PR layer), and 2) establishing graft integration (useful synapse formation) and vision benefit. In preparation for commercialization, our multidisciplinary team, representing three Canadian universities (UBC, SFU, and DU), have spun-off the company, VisuCyte Therapeutics Inc., which is being incubated at UBC.
1 April 2018
28 February 2019
2018
Shirley Mei (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Équipes de recherche sur les maladies
McIntyre
Cochercheur
Lauralyn McIntyre , Shirley Mei
44 278
Cellular Immunotherapy for Septic Shock (CISS2): A phase II multicentre clinical trial
Septicémie
Cellular Immunotherapy for Septic Shock (CISS): A Phase II Multicentre Clinical Trial
1 April 2018
28 February 2019
2018
Lauralyn McIntyre (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Équipes de recherche sur les maladies
McIntyre
Chercheur principal
Lauralyn McIntyre , Shirley Mei
155 722
Cellular Immunotherapy for Septic Shock (CISS2): A phase II multicentre clinical trial
Septicémie
Cellular Immunotherapy for Septic Shock (CISS): A Phase II Multicentre Clinical Trial
1 April 2018
28 February 2019
2018
Cindi Morshead (C)
University of Toronto
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 223
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Jing Wang (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Paul Frankland (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
David Kaplan (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Ann Yeh (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Doug Munoz (C)
Queen's University
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Donald Mabbott (C)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Freda Miller (P)
Hospital for Sick Children
Équipes de recherche sur les maladies
Miller
Chercheur principal
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 222
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Wolfram Tetzlaff (C)
University of British Columbia
Équipes de recherche sur les maladies
Miller
Cochercheur
Freda Miller, Donald Mabbott, Cindi Morshead, Doug Munoz, Ann Yeh, David Kaplan, Paul Frankland, Jing Wang, Wolfram Tetzlaff
22 223
Pharmacological recruitment of endogenous neural precursors to promote pediatric white matter repair
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 April 2018
28 February 2019
2018
Massimiliano Paganelli (P)
CHU Sainte-Justine
Équipes de recherche sur les maladies
Paganelli
Chercheur principal
Massimiliano Paganelli
100 000
Safety and efficacy of stem cell- derived Encapsulated Liver Tissue to treat liver failure without immunosuppression
Insuffisance hépatique
One in ten Canadians is affected by liver disease. The standard of care for liver failure (the common outcome of any progressive liver disease) is liver transplantation, but only 400 transplants are performed each year in Canada for over 5000 liver deaths/year. Thus, there is an urgent need for new therapies capable of replacing liver functions in children and adults with liver failure. Thanks to a grant from the Stem Cell Network and to a team of internationally-renowned experts, in less than one year we developed an innovative stem cell-derived product capable of effectively performing the functions of the human liver. The final aim of this multidisciplinary project is to develop such a product into a treatment to restore the lacking liver functions in patients with liver failure, improving survival and preventing/treating complications. We will thoroughly assess the potential of our stem cell-derived product (what we call the encapsulated liver tissue, or ELT) to purify the patients’ blood from toxic substances and synthesize proteins needed for vital functions, improving survival and preventing severe complications, without the risk of rejection (eliminating the need for lifelong immunosuppression). If successful, at the end of the study we will dispose of a safe and effective off-the-shelf, implantable product to potentially treat thousands of people with liver failure. We will then conduct thorough pre-clinical studies, in compliance with Health Canada requirements, in order to prepare for an early-phase clinical trial in the medium term (3 years). We already protected this intellectual property and, in collaboration with our partners, we will work to translate the ELT to the industry through a start-up company creation or out-licensing. If successful, this project will deliver an innovative product to treat acute, chronic or acute-on-chronic liver failure without immunosuppression, with the potential of saving hundreds of thousands of patients worldwide.
1 April 2018
28 February 2019
2018
Gregory Korbutt (C)
University of Alberta
Équipes de recherche sur les maladies
Shapiro
Cochercheur
James Shapiro, Gregory Korbutt
50 000
Development of a novel stem cell- derived transplant modality for type 1 diabetes
Diabète
Islet transplantation has demonstrated that the replacement of insulin-producing β-cells is an effective means of restoring blood glucose control in patients with type 1 diabetes (T1D), especially in subjects at risk of severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors must be addressed. Remarkable progress has occurred in stem cell technology regarding clinical-grade insulin-producing cells with the capacity for limitless expansion; solving inadequate organ donor supply. Our group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s (world leader in stem cell development) VC-01 and VC-02 combination products in a cohort of patients with T1D in Edmonton. This trial examines the ability of ViaCyte’s insulin-producing pancreatic endoderm cells (PEC) to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into National and Worldwide clinical practice. The objective of this SCN proposal is to use an innovative approach to bioengineer a retrievable, functionalized scaffold, that houses and supports long-term function of ViaCyte’s PEC cells to treat T1D. The Disease Team consists of Dr. James Shapiro and Dr. Gregory Korbutt. As a clinical scientist and Director of the Clinical Islet Transplant Program, Dr. Shapiro is internationally recognized for his pioneering contributions to the development of the ‘Edmonton Protocol’, and is currently leading thirteen clinical trials in islet, stem cell and liver transplantation. Co-PI, Dr. Korbutt, is the Scientific Director of the cGMP “Alberta Cell Therapy Manufacturing Facility” for cell and tissue production, with significant expertise in islet biology and transplantation. The Team has also established a productive collaboration the Ingenuity Lab Nanotechnology Accelerator, with Dr. Puru Kuppan, a multidisciplinary R&D initiative focused on groundbreaking nanotechnology advances. Strategies for further commercialization will be conducted with support from TEC Edmonton, whom has provided support in filing US and Canadian provisional patents for this technology. This research proposal has been developed by a group of investigators offering unique expertise in clinical islet transplantation and stem cell biology, as well as biomaterial engineering expertise. With an active clinical islet transplant program in Edmonton, a new cGMP facility for the clinical grade production of cells, and the bioactive scaffold design expertise of the Ingenuity’s Laboratory, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 April 2018
28 February 2019
2018
James Shapiro (P)
University of Alberta
Équipes de recherche sur les maladies
Shapiro
Chercheur principal
James Shapiro, Gregory Korbutt
50 000
Development of a novel stem cell- derived transplant modality for type 1 diabetes
Diabète
Islet transplantation has demonstrated that the replacement of insulin-producing β-cells is an effective means of restoring blood glucose control in patients with type 1 diabetes (T1D), especially in subjects at risk of severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors must be addressed. Remarkable progress has occurred in stem cell technology regarding clinical-grade insulin-producing cells with the capacity for limitless expansion; solving inadequate organ donor supply. Our group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s (world leader in stem cell development) VC-01 and VC-02 combination products in a cohort of patients with T1D in Edmonton. This trial examines the ability of ViaCyte’s insulin-producing pancreatic endoderm cells (PEC) to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into National and Worldwide clinical practice. The objective of this SCN proposal is to use an innovative approach to bioengineer a retrievable, functionalized scaffold, that houses and supports long-term function of ViaCyte’s PEC cells to treat T1D. The Disease Team consists of Dr. James Shapiro and Dr. Gregory Korbutt. As a clinical scientist and Director of the Clinical Islet Transplant Program, Dr. Shapiro is internationally recognized for his pioneering contributions to the development of the ‘Edmonton Protocol’, and is currently leading thirteen clinical trials in islet, stem cell and liver transplantation. Co-PI, Dr. Korbutt, is the Scientific Director of the cGMP “Alberta Cell Therapy Manufacturing Facility” for cell and tissue production, with significant expertise in islet biology and transplantation. The Team has also established a productive collaboration the Ingenuity Lab Nanotechnology Accelerator, with Dr. Puru Kuppan, a multidisciplinary R&D initiative focused on groundbreaking nanotechnology advances. Strategies for further commercialization will be conducted with support from TEC Edmonton, whom has provided support in filing US and Canadian provisional patents for this technology. This research proposal has been developed by a group of investigators offering unique expertise in clinical islet transplantation and stem cell biology, as well as biomaterial engineering expertise. With an active clinical islet transplant program in Edmonton, a new cGMP facility for the clinical grade production of cells, and the bioactive scaffold design expertise of the Ingenuity’s Laboratory, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 April 2018
28 February 2019
2018
Bruce Verchere (P)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Chercheur principal
Bruce Verchere, Timothy Kieffer, Ann Yeh, Megan Levings
80 000
Genetic manipulation of hES- derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 April 2018
28 February 2019
2018
Francis Lynn (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Timothy Kieffer, Ann Yeh, Megan Levings
80 000
Genetic manipulation of hES- derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 April 2018
28 February 2019
2018
Timothy Kieffer (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Timothy Kieffer, Ann Yeh, Megan Levings
20 000
Genetic manipulation of hES- derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 April 2018
28 February 2019
2018
Megan Levings (C)
University of British Columbia
Équipes de recherche sur les maladies
Verchere
Cochercheur
Bruce Verchere, Timothy Kieffer, Ann Yeh, Megan Levings
20 000
Genetic manipulation of hES- derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 April 2018
28 February 2019
2018
Jean-François Bouchard (C)
Université de Montréal
Équipes de recherche sur les maladies
Bernier
Cochercheur
Gilbert Bernier, May Griffith, Jean-François Bouchard
25 000
Human macula transplantation in a pre-clinical model of severe macular degeneration in macaques
Oculaire
The major technological breakthrough of the description of “Yamanaka factors” enables the reprogramming of human cells into pluripotent stem cells appropriate for deriving a diversity of human cells that have previously been inaccessible for study. This includes the study of brain cells, such as neurons and several glia cell types, that are notoriously difficult to access. The ependymal cell – the brain’s epithelial barrier cell, lines the entire ventricular system and is critically understudied largely due to a lack of reliable cellular models for their study. Ependymal cells regulate cerebrospinal fluid (CSF) circulation; and over the last decade, their role in the maintenance of CSF homeostasis is becoming much more appreciated. There is an overwhelming number of neurological conditions and diseases that are subject to ependymal cell abnormalities, which can subsequently interfere with developmental processes, regenerative mechanisms and contribute to disease progression.
Developing a robust method for generating ependymal cell cultures would not only greatly benefit my research program but would also have a wider impact on the research community, given no such method currently exists. Our objective is to use human iPSCs to develop a robust method for the routine culturing of human ependymal cells. In the process of developing this translational method, we will gain a greater understanding of the developmental timelines of human ependymal cells and apply this knowledge to better inform their regenerative potential and how they may become compromised in disease. We can use this system to understand how genes and environment interact in diseases impacting ependymal cells or impacted by ependymal cells - an accomplishment in both the fields of stem cell biology and ependymal cell biology. Ultimately, we will generate methodology that will be disseminated openly via Open-Access journals and at conferences. Along with our team of iPSC and glia experts, Drs Thomas Durcan and Luke Healy, as well as ependymal cell biologist, Jo Anne Stratton, we are well positioned to execute this project. Finally, the McGill Regenerative Network is an instrumental partner for this project, where they will support trainee stipend costs and provide network resources.
1 April 2018
28 February 2019
2018
May Griffith (C)
Université de Montréal
Équipes de recherche sur les maladies
Bernier
Cochercheur
Gilbert Bernier, May Griffith, Jean-François Bouchard
25 000
Human macula transplantation in a pre-clinical model of severe macular degeneration in macaques
Oculaire
The major technological breakthrough of the description of “Yamanaka factors” enables the reprogramming of human cells into pluripotent stem cells appropriate for deriving a diversity of human cells that have previously been inaccessible for study. This includes the study of brain cells, such as neurons and several glia cell types, that are notoriously difficult to access. The ependymal cell – the brain’s epithelial barrier cell, lines the entire ventricular system and is critically understudied largely due to a lack of reliable cellular models for their study. Ependymal cells regulate cerebrospinal fluid (CSF) circulation; and over the last decade, their role in the maintenance of CSF homeostasis is becoming much more appreciated. There is an overwhelming number of neurological conditions and diseases that are subject to ependymal cell abnormalities, which can subsequently interfere with developmental processes, regenerative mechanisms and contribute to disease progression.
Developing a robust method for generating ependymal cell cultures would not only greatly benefit my research program but would also have a wider impact on the research community, given no such method currently exists. Our objective is to use human iPSCs to develop a robust method for the routine culturing of human ependymal cells. In the process of developing this translational method, we will gain a greater understanding of the developmental timelines of human ependymal cells and apply this knowledge to better inform their regenerative potential and how they may become compromised in disease. We can use this system to understand how genes and environment interact in diseases impacting ependymal cells or impacted by ependymal cells - an accomplishment in both the fields of stem cell biology and ependymal cell biology. Ultimately, we will generate methodology that will be disseminated openly via Open-Access journals and at conferences. Along with our team of iPSC and glia experts, Drs Thomas Durcan and Luke Healy, as well as ependymal cell biologist, Jo Anne Stratton, we are well positioned to execute this project. Finally, the McGill Regenerative Network is an instrumental partner for this project, where they will support trainee stipend costs and provide network resources.
1 April 2018
28 February 2019
2018
Gilbert Bernier (P)
Hôpital Maisonneuve-Rosemont
Équipes de recherche sur les maladies
Bernier
Chercheur principal
Gilbert Bernier, May Griffith, Jean-François Bouchard
150 000
Human macula transplantation in a pre-clinical model of severe macular degeneration in macaques
Oculaire
The major technological breakthrough of the description of “Yamanaka factors” enables the reprogramming of human cells into pluripotent stem cells appropriate for deriving a diversity of human cells that have previously been inaccessible for study. This includes the study of brain cells, such as neurons and several glia cell types, that are notoriously difficult to access. The ependymal cell – the brain’s epithelial barrier cell, lines the entire ventricular system and is critically understudied largely due to a lack of reliable cellular models for their study. Ependymal cells regulate cerebrospinal fluid (CSF) circulation; and over the last decade, their role in the maintenance of CSF homeostasis is becoming much more appreciated. There is an overwhelming number of neurological conditions and diseases that are subject to ependymal cell abnormalities, which can subsequently interfere with developmental processes, regenerative mechanisms and contribute to disease progression.
Developing a robust method for generating ependymal cell cultures would not only greatly benefit my research program but would also have a wider impact on the research community, given no such method currently exists. Our objective is to use human iPSCs to develop a robust method for the routine culturing of human ependymal cells. In the process of developing this translational method, we will gain a greater understanding of the developmental timelines of human ependymal cells and apply this knowledge to better inform their regenerative potential and how they may become compromised in disease. We can use this system to understand how genes and environment interact in diseases impacting ependymal cells or impacted by ependymal cells - an accomplishment in both the fields of stem cell biology and ependymal cell biology. Ultimately, we will generate methodology that will be disseminated openly via Open-Access journals and at conferences. Along with our team of iPSC and glia experts, Drs Thomas Durcan and Luke Healy, as well as ependymal cell biologist, Jo Anne Stratton, we are well positioned to execute this project. Finally, the McGill Regenerative Network is an instrumental partner for this project, where they will support trainee stipend costs and provide network resources.
1 April 2018
28 February 2019
2018
Timothy Caulfield (P)
University of Alberta
Recherche d’impact, politique publique
Caulfield
Chercheur principal
Timothy Caulfield
40 000
The Next Step: Specific Strategies for Addressing the Marketing of Unproven Stem Cell Therapies
Thérapies non éprouvées
The marketing of unproven stem cells remains a significant and growing issue which necessitates a broad regulatory response. In Canada, there is a need for improved regulatory clarity to address gaps in regulation. Increasing attention has been given to the problem of unproven stem cell therapies, including growing recognition that clinics in Canada are offering unproven treatments and products.[1] A project that focuses on concrete regulatory strategies is both needed and timely. With this project we aim to complete unique legal research and, in addition, bring together our team’s past work on regulatory strategies and on public representations to produce comprehensive recommendations regarding how Canada should respond to the challenges associated with the marketing of stem cell research, technologies and therapies.
Specifically, we will conduct scholarly legal research – which a particular emphasis on the legal standard of care, an unexplored aspect of the Canadian regulatory landscape – and build on our past work to produce actionable conclusions. We will make clear recommendations about how Canadian law applies to unproven stem cell therapies and the marketing thereof, and how the law should be utilized to help curb potentially harmful practices.
The goals of our research are: to determine how and when professional regulators (such as Colleges of Physicians and Surgeons, provincial naturopath associations and other similar bodies) should respond to members of their profession offering and advertising stem cell therapies; and to address multiple legal questions in relation to unproven stem cell therapies, such as the effects of legal standard of care, the status of practitioners offering these therapies as potentially negligent or possibly as a legally protected “respected minority”, the interaction of federal regulations with the experimental treatments, and the sufficiency of those regulations as they relate to health product and services classifications, among other things.
1 April 2018
28 February 2019
2018
Bartha Knoppers (P)
Université McGill
Recherche d’impact, politique publique
Knoppers
Chercheur principal
Bartha Knoppers
39 736
Reforming Canadian Stem Cell Policy: Moving Beyond the Assisted Human Reproduction Act (AHRA)
QEJS, questions éthiques, juridiques et sociales
Scientific developments and their expanding international scope (from legitimate research to ‘tourism’) demonstrate the pressing need to continue the socio-ethical and policy discussions surrounding the often interconnected fields of stem cells (SC) and genetic and reproductive technologies. There is a critical need for policy guidance adaptive to the complexities of this emerging field of “cellular genomics.” Reform of the Assisted Human Reproduction Act (AHRA) remains uncharted. On September 30th, 2016, the Canadian Government announced its intention to strengthen and clarify the policy frameworks regulating assisted human reproduction. Prompted by these developments, from 2016-2017, the Centre of Genomics and Policy at McGill University, together with the SCN and the collaborators named in this grant (“Policy Group”) sponsored four workshops to assess the adequacy of existing regulatory frameworks. The outcome of the workshops is a series of published recommendations leading into a Consensus Statement (to be released November 2017 at the Till & McCulloch Meeting) to guide the much-needed clarification and reform of the AHRA. Another key outcome of this process was future agenda setting that highlighted the necessity to move from policy development to consultation and validation. Thus, the core of this application by the Policy Group centers on the continuation of the SCN’s policy leadership legacy.
We propose a critical, forward-looking series of meetings and exchanges in partnership with Canadian stakeholders with the overall objective of consulting and validating our recommendations, so as to propose effective policy translation. This approach will be supported by the active involvement of representative stakeholders/professional organizations such as the Canadian Medical Association (CMA), the Canadian College of Medical Geneticists (CCMG-CCGM) and governmental agencies (e.g. Health Canada), as well as academic-industry organizations such as the Centre for Commercialization of Regenerative Medicine (CCRM).
1 April 2018
28 February 2019
2018
Eric Marsault (C)
University of Sherbrooke
Recherche d’impact, translation
Bentzinger
Cochercheur
Florian Bentzinger, Mannix Auger-Messier, Eric Marsault
9 000
Apelinergic Compounds for the treatment of muscular dystrophy
Dystrophie musculaire
The function of muscle stem cells (MuSCs) and thereby the regenerative capacity of skeletal muscle is compromised in muscular dystrophies (MDs). In the majority of MDs, heterogeneous mutations lead to muscle fibers that are structurally more fragile and tend to rupture under the mechanical stress of contraction. The presence of several foci of injury in dystrophic muscle, which develop asynchronously and induce chronic inflammation, alter the tissue through thickening and stiffening of the extracellular matrix and by decreasing vascular support. These sustained changes in the extracellular milieu impair the function of MuSCs up to the point where they can no longer compensate for the continuous fiber degeneration. Thus, therapeutic normalization of the tissue environment and remobilization of MuSCs is emerging as a promising approach to restore or maintain muscle functionality in MDs.
Recent proteomic screens for circulating positive modulators of MuSC function in human serum have identified the peptide hormone Apelin. The active form of Apelin containing 13 amino acids (AP13) is highly efficient in stimulating MuSC proliferation and differentiation. AP13 has also been shown to reduce fibrosis in several organs and has angiogenic properties. Thus, apelinergic signaling ameliorates key hallmarks of the regenerative pathology in MDs, including MuSC dysfunction, fibrosis and reduced tissue vascularization. Based on the structure–activity relationship of AP13 with its receptor, we have generated a library of ~70 analogues with unnatural amino acids displaying increased Apelin receptor binding affinity and plasma stability. Here we propose to characterize and test these compounds for their efficacy in stimulating the function of MuSC derived cells in-vitro and in a preclinical model of congenital MD. The identification of systemically administrable compounds with the ability to restore MuSC function in MD will provide new composition of matter for IP protection that will facilitate industry partnering and progression towards clinical studies.
1 April 2018
28 February 2019
2018
Mannix Auger-Messier (C)
University of Sherbrooke
Recherche d’impact, translation
Bentzinger
Cochercheur
Florian Bentzinger, Mannix Auger-Messier, Eric Marsault
7 000
Apelinergic Compounds for the treatment of muscular dystrophy
Dystrophie musculaire
The function of muscle stem cells (MuSCs) and thereby the regenerative capacity of skeletal muscle is compromised in muscular dystrophies (MDs). In the majority of MDs, heterogeneous mutations lead to muscle fibers that are structurally more fragile and tend to rupture under the mechanical stress of contraction. The presence of several foci of injury in dystrophic muscle, which develop asynchronously and induce chronic inflammation, alter the tissue through thickening and stiffening of the extracellular matrix and by decreasing vascular support. These sustained changes in the extracellular milieu impair the function of MuSCs up to the point where they can no longer compensate for the continuous fiber degeneration. Thus, therapeutic normalization of the tissue environment and remobilization of MuSCs is emerging as a promising approach to restore or maintain muscle functionality in MDs.
Recent proteomic screens for circulating positive modulators of MuSC function in human serum have identified the peptide hormone Apelin. The active form of Apelin containing 13 amino acids (AP13) is highly efficient in stimulating MuSC proliferation and differentiation. AP13 has also been shown to reduce fibrosis in several organs and has angiogenic properties. Thus, apelinergic signaling ameliorates key hallmarks of the regenerative pathology in MDs, including MuSC dysfunction, fibrosis and reduced tissue vascularization. Based on the structure–activity relationship of AP13 with its receptor, we have generated a library of ~70 analogues with unnatural amino acids displaying increased Apelin receptor binding affinity and plasma stability. Here we propose to characterize and test these compounds for their efficacy in stimulating the function of MuSC derived cells in-vitro and in a preclinical model of congenital MD. The identification of systemically administrable compounds with the ability to restore MuSC function in MD will provide new composition of matter for IP protection that will facilitate industry partnering and progression towards clinical studies.
1 April 2018
28 February 2019
2018
Florian Bentzinger (P)
University of Sherbrooke
Recherche d’impact, translation
Bentzinger
Chercheur principal
Florian Bentzinger, Mannix Auger-Messier, Eric Marsault
83 000
Apelinergic Compounds for the treatment of muscular dystrophy
Dystrophie musculaire
The function of muscle stem cells (MuSCs) and thereby the regenerative capacity of skeletal muscle is compromised in muscular dystrophies (MDs). In the majority of MDs, heterogeneous mutations lead to muscle fibers that are structurally more fragile and tend to rupture under the mechanical stress of contraction. The presence of several foci of injury in dystrophic muscle, which develop asynchronously and induce chronic inflammation, alter the tissue through thickening and stiffening of the extracellular matrix and by decreasing vascular support. These sustained changes in the extracellular milieu impair the function of MuSCs up to the point where they can no longer compensate for the continuous fiber degeneration. Thus, therapeutic normalization of the tissue environment and remobilization of MuSCs is emerging as a promising approach to restore or maintain muscle functionality in MDs.
Recent proteomic screens for circulating positive modulators of MuSC function in human serum have identified the peptide hormone Apelin. The active form of Apelin containing 13 amino acids (AP13) is highly efficient in stimulating MuSC proliferation and differentiation. AP13 has also been shown to reduce fibrosis in several organs and has angiogenic properties. Thus, apelinergic signaling ameliorates key hallmarks of the regenerative pathology in MDs, including MuSC dysfunction, fibrosis and reduced tissue vascularization. Based on the structure–activity relationship of AP13 with its receptor, we have generated a library of ~70 analogues with unnatural amino acids displaying increased Apelin receptor binding affinity and plasma stability. Here we propose to characterize and test these compounds for their efficacy in stimulating the function of MuSC derived cells in-vitro and in a preclinical model of congenital MD. The identification of systemically administrable compounds with the ability to restore MuSC function in MD will provide new composition of matter for IP protection that will facilitate industry partnering and progression towards clinical studies.
1 April 2018
28 February 2019
2018
Mick Bhatia (P)
McMaster University
Recherche d’impact, translation
Bhatia
Chercheur principal
Mick Bhatia
100 000
Identification of kinases and their target substrates in early human PSC specification
Kinases
Human stem cells (SCs) are unique in their ability to generate mature cells that have specific function for organs or tissues. Although adult SCs, like blood SCs in the bone marrow, have been used clinically for life supporting transplants, another type of human SC termed pluripotent stem cell (PSC) still requires further understanding for translational applications in patients. Unlike adult SCs, PSCs have the ability to generate all types of cells that make up any organ or tissue. Accordingly, PSCs may hold the greatest potential due to its broader ability to generate all types of cells. Unfortunately, controlling PSCs to become one cell type vs. another e.g. a blood cell vs. a neuron, is a process called “differentiation” that is very difficult to achieve. Human PSCs tend to change into multiple cell types randomly, which prevents isolation or purity of the cell type desired. This reduces the efficiency of generating mature cells that in turn makes the process prohibitively expensive. Our proposal approaches this problem by using chemical drugs that prevent the function of key proteins called “Kinases” that are responsible for relaying signals from the outside of the cell to the inside. These drugs have been well recognized and used to grow PSCs for years, but strangely have never been systematically tested in controlling PSC differentiation. We will combine McMaster’s ability to test human PSCs for differentiation, with the Ontario Institute for Cancer Research’s (OICR) uniquely developed set of drugs that inhibit kinase proteins. Drugs that enhance control of PSC differentiation compared to current standards will have immediate translational potential in applications of more effective methods to generate mature cells for therapy or disease modeling. OICR is vested in developing chemical/drug means for human disease applications and is strongly positioned to move results to its established private sector receptors.
1 April 2018
28 February 2019
2018
Nicolas Dumont (P)
CHU Sainte-Justine
Recherche d’impact, translation
Dumont
Chercheur principal
Nicolas Dumont
100 000
Targeting muscle stem cells to mitigate Duchenne muscular dystrophy
Duchenne muscular dystrophy is a severe childhood disease characterized by progressive and irreversible muscle wasting. Our recent findings indicate that the function of muscle stem cells, the engine of muscle repair, is impaired in this disease. Therefore, new therapeutic approaches must target muscle stem cells to mitigate the disease. To date, glucocorticoids are the only drugs that can temporarily slow down muscle wasting in Duchenne muscular dystrophy by dampening the chronic inflammatory process; however, they also have detrimental side effects that impair muscle stem cell function and stimulate long-term muscle wasting. Therefore, there is room for improvement and for the development of a more efficient therapy for this severe disease. Our research program investigates the impact of a new class of omega-3 or omega-6 derived mediators for the treatment of Duchenne muscular dystrophy. These molecules, named specialized pro-resolving mediators, have a potent ability to resolve inflammation, without the harmful side effects, and they could directly stimulate muscle stem cell activity and promote muscle healing. The proposed research project aims to screen for a variety of these mediators to identify the most potent compounds stimulating muscle stem cell function. The therapeutic efficacy of the lead compounds will be validated in vivo, with the financial support of the Grand défi Pierre Lavoie Foundation on rare diseases. The Research Center and the Foundation of the CHU Sainte-Justine are also partners in this project; and their support, together with the dynamic team of clinicians and translational researchers, will be instrumental in the translational stream. Altogether, with their ability to dampen inflammation and simultaneously restore muscle stem cell functions, the specialized pro-resolving mediators have the potential to preserve dystrophic muscle function overtime, improve the quality of life and the life expectancy of the patients suffering from Duchenne muscular dystrophy.
1 April 2018
28 February 2019
2018
John Hassell (P)
McMaster University
Recherche d’impact, translation
Hassell
Chercheur principal
John Hassell
99 500
HTR5A as a target for anticancer stem cell drug discovery
Cancer du sein
Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths. Unfortunately, despite improved screening methods and new, targeted therapies the worldwide incidence of breast cancer is increasing. Moreover, drugs commonly used to treat breast cancer often do not achieve long-lasting remissions. Tumor recurrence is due to infrequent breast tumor cells, known as breast tumor initiating cells (BTIC). BTIC are functionally defined as the cells in tumors capable of seeding the growth of new tumors after transplantation into mice.
BTIC are resistant to chemotherapy and thus are responsible for tumor recurrence in patients. Ironically the vast majority of breast tumor cells are not capable of initiating tumor growth in mice. However, the “non-tumorigenic” tumor cells are sensitive to chemotherapy, which explains why tumors generally shrink after administering chemotherapy to patients.
Our overarching goal is to develop new therapies that eliminate BTIC to provide more durable breast cancer remissions.
We recently discovered that drugs, which inhibit the synthesis or activity of serotonin, eliminate BTIC and work in combination with chemotherapy to dramatically shrink breast tumors. Serotonin is made in select nerve cells and then released to relay signals to another specialized nerve cell where it exerts its activity by binding to receptors on the surface of this cell. However, serotonin is also found in tissues outside the nervous system and plays a role in normal breast development. BTIC are also known as breast cancer stem cells because they share properties with breast stem cells, which are required for breast development.
Our proposal seeks to determine whether one of the serotonin receptors, HTR5A, which we have implicated in breast cancer, is required for BTIC survival and whether chemicals that specifically block the receptor can be developed into drugs to treat breast cancer.
1 April 2018
28 February 2019
2020
Tim Kieffer (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Tim Kieffer
40 000
Genetic manipulation of hES-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 January 2020
31 January 2022
2020
Megan Levings (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Tim Kieffer
40 000
Genetic manipulation of hES-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 January 2020
31 January 2022
2020
Francis Lynn (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Tim Kieffer
228 000
Genetic manipulation of hES-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 January 2020
31 January 2022
2020
Bruce Verchere (P)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Chercheur principal
Bruce Verchere, Francis Lynn, Megan Levings, Tim Kieffer
292 000
Genetic manipulation of hES-derived insulin-producing cells to improve graft outcomes
Diabète
A cure for type 1 diabetes may lie in the replacement of insulin-producing cells by transplantation. Hundreds of patients worldwide (including 80 in Vancouver) have received transplants of islets–clusters of insulin-producing cells in the pancreas–enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of insulin-producing cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function.
In the first year of SCN support, our team genetically engineered human embryonic stem cells so that they (i) no longer produced a protein that is toxic in diabetes and cell transplants; and (ii) produce a protein which turns off the immune attack on transplanted cells. In the second year of SCN support, we propose to differentiate these genetically engineered stem cells into human insulin-producing cells and to test them following transplantation into mouse models of diabetes.
Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that can be tested in clinical trial in a few years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 January 2020
31 January 2022
2020
Nilesh Ghugre (C)
University of Toronto
Subventions de soutien à l’accélération de la transposition clinique
Laflamme
Cochercheur
Michael Laflamme, Graham Wright, Nilesh Ghugre
74 592
Heart Regeneration with Mature Ventricular Cardiomyocytes from Human Pluripotent Stem Cells
Cardiaque
Each year 70,000 Canadians suffer a heart attack (also known as a myocardial infarction or MI) accounting for the majority of the 50,000 new cases of heart failure diagnosed annually. After an MI, the damaged heart muscle is replaced by non-contractile scar tissue, and current treatment options for treating post-MI heart failure are aimed at reducing symptoms and disease progress, not restoring lost myocardium. Hence, the ability to “remuscularize” the infarct zone via the transplantation of cardiomyocytes (heart muscle cells) derived from human pluripotent stem cells (hPSCs) represents a potentially revolutionary new therapy for patients suffering from this disease with very high morbidity and mortality. Toward this goal, this proposal brings together a diverse team of investigators with complementary expertise in stem cell and developmental biology (Gordon Keller), cell transplantation (Michael Laflamme & Ren-Ke Li), cardiac imaging in large-animal models of myocardial infarction (Graham Wright & Nilesh Ghugre) and the surgical care of patients with ischemic heart disease (Terrence Yau). In past work, we have translated our protocols for the cardiogenic differentiation of hPSCs from the lab bench to large-scale production, and we have partnered with BlueRock Therapeutics, a recently launched biotechnology company with Toronto-based cell manufacturing facilities to further upscale and commercialize these technologies. The present application builds on these advances and specifically focuses on testing a more recently developed mature hPSC-derived cardiomyocyte population that we predict will greatly improve the safety and efficacy of cell transplantation. We will test these mature hPSC-derived cardiomyocytes in a translationally-relevant porcine model of post-infarct heart failure and will employ comprehensive endpoints including histology (host and graft tissue structure), MRI (infarct size and contractile function), as well as ECG recording and mapping studies (electrical function). The successful completion of this work will help advance this novel cell product toward a first-in-human clinical trial in post-MI heart failure and further establish Canada’s leadership role in cardiac regenerative medicine.
1 January 2020
31 January 2022
2020
Graham Wright (C)
University of Toronto
Subventions de soutien à l’accélération de la transposition clinique
Laflamme
Cochercheur
Michael Laflamme, Graham Wright, Nilesh Ghugre
22 704
Heart Regeneration with Mature Ventricular Cardiomyocytes from Human Pluripotent Stem Cells
Cardiaque
Each year 70,000 Canadians suffer a heart attack (also known as a myocardial infarction or MI) accounting for the majority of the 50,000 new cases of heart failure diagnosed annually. After an MI, the damaged heart muscle is replaced by non-contractile scar tissue, and current treatment options for treating post-MI heart failure are aimed at reducing symptoms and disease progress, not restoring lost myocardium. Hence, the ability to “remuscularize” the infarct zone via the transplantation of cardiomyocytes (heart muscle cells) derived from human pluripotent stem cells (hPSCs) represents a potentially revolutionary new therapy for patients suffering from this disease with very high morbidity and mortality. Toward this goal, this proposal brings together a diverse team of investigators with complementary expertise in stem cell and developmental biology (Gordon Keller), cell transplantation (Michael Laflamme & Ren-Ke Li), cardiac imaging in large-animal models of myocardial infarction (Graham Wright & Nilesh Ghugre) and the surgical care of patients with ischemic heart disease (Terrence Yau). In past work, we have translated our protocols for the cardiogenic differentiation of hPSCs from the lab bench to large-scale production, and we have partnered with BlueRock Therapeutics, a recently launched biotechnology company with Toronto-based cell manufacturing facilities to further upscale and commercialize these technologies. The present application builds on these advances and specifically focuses on testing a more recently developed mature hPSC-derived cardiomyocyte population that we predict will greatly improve the safety and efficacy of cell transplantation. We will test these mature hPSC-derived cardiomyocytes in a translationally-relevant porcine model of post-infarct heart failure and will employ comprehensive endpoints including histology (host and graft tissue structure), MRI (infarct size and contractile function), as well as ECG recording and mapping studies (electrical function). The successful completion of this work will help advance this novel cell product toward a first-in-human clinical trial in post-MI heart failure and further establish Canada’s leadership role in cardiac regenerative medicine.
1 January 2020
31 January 2022
2020
Michael Laflamme (P)
University Health Network
Subventions de soutien à l’accélération de la transposition clinique
Laflamme
Chercheur principal
Michael Laflamme, Graham Wright, Nilesh Ghugre
502 389
Heart Regeneration with Mature Ventricular Cardiomyocytes from Human Pluripotent Stem Cells
Cardiaque
Each year 70,000 Canadians suffer a heart attack (also known as a myocardial infarction or MI) accounting for the majority of the 50,000 new cases of heart failure diagnosed annually. After an MI, the damaged heart muscle is replaced by non-contractile scar tissue, and current treatment options for treating post-MI heart failure are aimed at reducing symptoms and disease progress, not restoring lost myocardium. Hence, the ability to “remuscularize” the infarct zone via the transplantation of cardiomyocytes (heart muscle cells) derived from human pluripotent stem cells (hPSCs) represents a potentially revolutionary new therapy for patients suffering from this disease with very high morbidity and mortality. Toward this goal, this proposal brings together a diverse team of investigators with complementary expertise in stem cell and developmental biology (Gordon Keller), cell transplantation (Michael Laflamme & Ren-Ke Li), cardiac imaging in large-animal models of myocardial infarction (Graham Wright & Nilesh Ghugre) and the surgical care of patients with ischemic heart disease (Terrence Yau). In past work, we have translated our protocols for the cardiogenic differentiation of hPSCs from the lab bench to large-scale production, and we have partnered with BlueRock Therapeutics, a recently launched biotechnology company with Toronto-based cell manufacturing facilities to further upscale and commercialize these technologies. The present application builds on these advances and specifically focuses on testing a more recently developed mature hPSC-derived cardiomyocyte population that we predict will greatly improve the safety and efficacy of cell transplantation. We will test these mature hPSC-derived cardiomyocytes in a translationally-relevant porcine model of post-infarct heart failure and will employ comprehensive endpoints including histology (host and graft tissue structure), MRI (infarct size and contractile function), as well as ECG recording and mapping studies (electrical function). The successful completion of this work will help advance this novel cell product toward a first-in-human clinical trial in post-MI heart failure and further establish Canada’s leadership role in cardiac regenerative medicine.
1 January 2020
31 January 2022
2020
Zachary Laksman (P)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Laksman
Chercheur principal
Zachary Laksman, Gordon Keller, Glen Tibbits, Liam Brunham
292 000
Pipeline towards stem cell driven personalized medicine for atrial fibrillation
Cardiaque; fibrillation auriculaire
Our international team of collaborators and industry partners are dedicated to delivering personalized therapy to patients with atrial fibrillation (AF). This first proof of principle study will take one family through the process of generating patient specific heart models, using both stem cell derived heart tissue and complex computational modeling, to identify therapies that have the most potential for benefit, while ultimately exposing individuals to the smallest risk of harm. Every step of this process requires unique expertise, technologic innovation, and provides for the opportunity for clinically impactful discovery. This can only be accomplished when clinicians, scientists, and industry partner together along a common vision, and focused on specific and tangible deliverables.
AF is the most common heart rhythm disorder, and has devastating consequences on patients and our health care system. While medications remain as first line therapy for AF, there has been an appalling paucity of new compounds over the last two decades. Current therapies remain ineffective, untargeted, and in many cases, unsafe. Companies have struggled to innovate and translate in this space because they have not had appropriate disease models before proceeding to expensive clinical trials. AF is a complex condition that requires the study of human heart tissue. We also know that changes in DNA have an important effect on the disease and its treatment.
Stem cell derived heart tissue has clearly superseded previous models of heart rhythm disorders, and is the only tool capable of studying a disease on a patient specific level. We generated the world’s first stem cell derived model of atrial fibrillation and have used this model system to replicate the clinical effects of commonly used heart medications, as well as show the potential toxic effects of a number of different compounds. Our team has grown to facilitate the requisite scaling of our model in order to provide a path towards clinically impactful deliverables. This includes expertise in bioengineered heart tissue, robotic automated high throughput screening, and whole organ computational modeling of disease. We are now uniquely positioned to provide clinically relevant solutions to patients suffering with atrial fibrillation.
1 January 2020
31 January 2022
2020
Gordon Keller (C)
University Health Network
Subventions de soutien à l’accélération de la transposition clinique
Laksman
Cochercheur
Zachary Laksman, Gordon Keller, Glen Tibbits, Liam Brunham
30 000
Pipeline towards stem cell driven personalized medicine for atrial fibrillation
Cardiaque
Our international team of collaborators and industry partners are dedicated to delivering personalized therapy to patients with atrial fibrillation (AF). This first proof of principle study will take one family through the process of generating patient specific heart models, using both stem cell derived heart tissue and complex computational modeling, to identify therapies that have the most potential for benefit, while ultimately exposing individuals to the smallest risk of harm. Every step of this process requires unique expertise, technologic innovation, and provides for the opportunity for clinically impactful discovery. This can only be accomplished when clinicians, scientists, and industry partner together along a common vision, and focused on specific and tangible deliverables.
AF is the most common heart rhythm disorder, and has devastating consequences on patients and our health care system. While medications remain as first line therapy for AF, there has been an appalling paucity of new compounds over the last two decades. Current therapies remain ineffective, untargeted, and in many cases, unsafe. Companies have struggled to innovate and translate in this space because they have not had appropriate disease models before proceeding to expensive clinical trials. AF is a complex condition that requires the study of human heart tissue. We also know that changes in DNA have an important effect on the disease and its treatment.
Stem cell derived heart tissue has clearly superseded previous models of heart rhythm disorders, and is the only tool capable of studying a disease on a patient specific level. We generated the world’s first stem cell derived model of atrial fibrillation and have used this model system to replicate the clinical effects of commonly used heart medications, as well as show the potential toxic effects of a number of different compounds. Our team has grown to facilitate the requisite scaling of our model in order to provide a path towards clinically impactful deliverables. This includes expertise in bioengineered heart tissue, robotic automated high throughput screening, and whole organ computational modeling of disease. We are now uniquely positioned to provide clinically relevant solutions to patients suffering with atrial fibrillation.
1 January 2020
31 January 2022
2020
Glen Tibbits (C)
Simon Fraser University
Subventions de soutien à l’accélération de la transposition clinique
Laksman
Cochercheur
Zachary Laksman, Gordon Keller, Glen Tibbits, Liam Brunham
152 000
Pipeline towards stem cell driven personalized medicine for atrial fibrillation
Cardiaque
Our international team of collaborators and industry partners are dedicated to delivering personalized therapy to patients with atrial fibrillation (AF). This first proof of principle study will take one family through the process of generating patient specific heart models, using both stem cell derived heart tissue and complex computational modeling, to identify therapies that have the most potential for benefit, while ultimately exposing individuals to the smallest risk of harm. Every step of this process requires unique expertise, technologic innovation, and provides for the opportunity for clinically impactful discovery. This can only be accomplished when clinicians, scientists, and industry partner together along a common vision, and focused on specific and tangible deliverables.
AF is the most common heart rhythm disorder, and has devastating consequences on patients and our health care system. While medications remain as first line therapy for AF, there has been an appalling paucity of new compounds over the last two decades. Current therapies remain ineffective, untargeted, and in many cases, unsafe. Companies have struggled to innovate and translate in this space because they have not had appropriate disease models before proceeding to expensive clinical trials. AF is a complex condition that requires the study of human heart tissue. We also know that changes in DNA have an important effect on the disease and its treatment.
Stem cell derived heart tissue has clearly superseded previous models of heart rhythm disorders, and is the only tool capable of studying a disease on a patient specific level. We generated the world’s first stem cell derived model of atrial fibrillation and have used this model system to replicate the clinical effects of commonly used heart medications, as well as show the potential toxic effects of a number of different compounds. Our team has grown to facilitate the requisite scaling of our model in order to provide a path towards clinically impactful deliverables. This includes expertise in bioengineered heart tissue, robotic automated high throughput screening, and whole organ computational modeling of disease. We are now uniquely positioned to provide clinically relevant solutions to patients suffering with atrial fibrillation.
1 January 2020
31 January 2022
2020
Liam Brunham (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Laksman
Cochercheur
Zachary Laksman, Gordon Keller, Glen Tibbits, Liam Brunham
112 000
Pipeline towards stem cell driven personalized medicine for atrial fibrillation
Cardiaque
Our international team of collaborators and industry partners are dedicated to delivering personalized therapy to patients with atrial fibrillation (AF). This first proof of principle study will take one family through the process of generating patient specific heart models, using both stem cell derived heart tissue and complex computational modeling, to identify therapies that have the most potential for benefit, while ultimately exposing individuals to the smallest risk of harm. Every step of this process requires unique expertise, technologic innovation, and provides for the opportunity for clinically impactful discovery. This can only be accomplished when clinicians, scientists, and industry partner together along a common vision, and focused on specific and tangible deliverables.
AF is the most common heart rhythm disorder, and has devastating consequences on patients and our health care system. While medications remain as first line therapy for AF, there has been an appalling paucity of new compounds over the last two decades. Current therapies remain ineffective, untargeted, and in many cases, unsafe. Companies have struggled to innovate and translate in this space because they have not had appropriate disease models before proceeding to expensive clinical trials. AF is a complex condition that requires the study of human heart tissue. We also know that changes in DNA have an important effect on the disease and its treatment.
Stem cell derived heart tissue has clearly superseded previous models of heart rhythm disorders, and is the only tool capable of studying a disease on a patient specific level. We generated the world’s first stem cell derived model of atrial fibrillation and have used this model system to replicate the clinical effects of commonly used heart medications, as well as show the potential toxic effects of a number of different compounds. Our team has grown to facilitate the requisite scaling of our model in order to provide a path towards clinically impactful deliverables. This includes expertise in bioengineered heart tissue, robotic automated high throughput screening, and whole organ computational modeling of disease. We are now uniquely positioned to provide clinically relevant solutions to patients suffering with atrial fibrillation.
1 January 2020
31 January 2022
2020
Greg Korbutt (C)
University of Alberta
Subventions de soutien à l’accélération de la transposition clinique
Nostro
Cochercheur
Cristina Nostro, Andrew Pepper, Greg Korbutt
150 000
Co-localized hiPSC-derived beta cells and immunosuppression-loaded micelles as a novel approach for T1D treatment
Diabète
Islet transplantation has demonstrated that the replacement of β-cells is an effective means to treat T1D patients with severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors and issues associated with harsh immunosuppression must be addressed. As a result of the remarkable progress in stem cell technology, the Edmonton Group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s VC-01 and VC-02 combination products in a cohort of patients with T1D. This trial examines the ability of ViaCyte’s pancreatic endoderm cells to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into clinical practice. Furthermore, the development of alternative GMP grade hiPSC-derived β-cells is imperative for the future of β-cell transplantation. The objective of this proposal is to use an innovative approach to bioengineer localized drug delivery platforms and to support long-term function of β-cells to treat T1D. This research proposal has been developed by a group of investigators (Nostro, Korbutt and Pepper) who each offer unique expertise in clinical islet transplantation, stem cell biology and biomaterial engineering. Dr. Nostro is internationally recognized for her pioneering contributions to the development of β-cell derived from hESC and hiPSC. Dr. Korbutt is the Scientific Director of the “Alberta Cell Therapy Manufacturing Facility” with significant expertise in islet biology and transplantation. Dr. Pepper is an expert in islet and stem cell transplantation with a clear and well-proven path to translate pre-clinical discovery into curative treatments for T1D patients. Strategies for further commercialization will be conducted with support from TEC Edmonton and UHN, who have provided support in filing US and Canadian provisional patents for this technology. With the advances and IPs in stem cell differentiaton to β-cells, an active clinical islet transplant program in Edmonton, a new cGMP facility for clinical grade production of cells, and the in-house drug delivery fabrication expertise, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 January 2020
31 January 2022
2020
Andrew Pepper (C)
University of Alberta
Subventions de soutien à l’accélération de la transposition clinique
Nostro
Cochercheur
Cristina Nostro, Andrew Pepper, Greg Korbutt
150 000
Co-localized hiPSC-derived beta cells and immunosuppression-loaded micelles as a novel approach for T1D treatment
Diabète
Islet transplantation has demonstrated that the replacement of β-cells is an effective means to treat T1D patients with severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors and issues associated with harsh immunosuppression must be addressed. As a result of the remarkable progress in stem cell technology, the Edmonton Group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s VC-01 and VC-02 combination products in a cohort of patients with T1D. This trial examines the ability of ViaCyte’s pancreatic endoderm cells to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into clinical practice. Furthermore, the development of alternative GMP grade hiPSC-derived β-cells is imperative for the future of β-cell transplantation. The objective of this proposal is to use an innovative approach to bioengineer localized drug delivery platforms and to support long-term function of β-cells to treat T1D. This research proposal has been developed by a group of investigators (Nostro, Korbutt and Pepper) who each offer unique expertise in clinical islet transplantation, stem cell biology and biomaterial engineering. Dr. Nostro is internationally recognized for her pioneering contributions to the development of β-cell derived from hESC and hiPSC. Dr. Korbutt is the Scientific Director of the “Alberta Cell Therapy Manufacturing Facility” with significant expertise in islet biology and transplantation. Dr. Pepper is an expert in islet and stem cell transplantation with a clear and well-proven path to translate pre-clinical discovery into curative treatments for T1D patients. Strategies for further commercialization will be conducted with support from TEC Edmonton and UHN, who have provided support in filing US and Canadian provisional patents for this technology. With the advances and IPs in stem cell differentiaton to β-cells, an active clinical islet transplant program in Edmonton, a new cGMP facility for clinical grade production of cells, and the in-house drug delivery fabrication expertise, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 January 2020
31 January 2022
2020
Cristina Nostro (P)
University Health Network
Subventions de soutien à l’accélération de la transposition clinique
Nostro
Chercheur principal
Cristina Nostro, Andrew Pepper, Greg Korbutt
300 000
Co-localized hiPSC-derived beta cells and immunosuppression-loaded micelles as a novel approach for T1D treatment
Diabète
Islet transplantation has demonstrated that the replacement of β-cells is an effective means to treat T1D patients with severe complications. If this therapeutic approach is to be expanded to a wider spectrum of patients, then the scarcity of organ donors and issues associated with harsh immunosuppression must be addressed. As a result of the remarkable progress in stem cell technology, the Edmonton Group is currently conducting a first-in-human pilot phase 1/2 clinical trials to test ViaCyte’s VC-01 and VC-02 combination products in a cohort of patients with T1D. This trial examines the ability of ViaCyte’s pancreatic endoderm cells to survive and function in an immune protecting device transplanted under the skin. However, there is an essential need to further optimize this approach prior to its translation into clinical practice. Furthermore, the development of alternative GMP grade hiPSC-derived β-cells is imperative for the future of β-cell transplantation. The objective of this proposal is to use an innovative approach to bioengineer localized drug delivery platforms and to support long-term function of β-cells to treat T1D. This research proposal has been developed by a group of investigators (Nostro, Korbutt and Pepper) who each offer unique expertise in clinical islet transplantation, stem cell biology and biomaterial engineering. Dr. Nostro is internationally recognized for her pioneering contributions to the development of β-cell derived from hESC and hiPSC. Dr. Korbutt is the Scientific Director of the “Alberta Cell Therapy Manufacturing Facility” with significant expertise in islet biology and transplantation. Dr. Pepper is an expert in islet and stem cell transplantation with a clear and well-proven path to translate pre-clinical discovery into curative treatments for T1D patients. Strategies for further commercialization will be conducted with support from TEC Edmonton and UHN, who have provided support in filing US and Canadian provisional patents for this technology. With the advances and IPs in stem cell differentiaton to β-cells, an active clinical islet transplant program in Edmonton, a new cGMP facility for clinical grade production of cells, and the in-house drug delivery fabrication expertise, this team is well positioned to rapidly transfer our novel findings to clinical trials.
1 January 2020
31 January 2022
2020
Vincent-Philippe Lavallee (C)
Université de Montréal
Subventions de soutien à l’accélération de la transposition clinique
Sauvageau
Cochercheur
Guy Sauvageau, Vincent-Philippe Lavallee
28 200
Bone marrow stem cell expansion with UM171: a better solution for patients and donors
Sang
Hematopoietic stem cells (HSC) transplantation is one of the most effective therapeutic strategies for patients with hematological malignancies. Largely supported by the SCN, our group of collaborators developed a cord blood (CB)-derived HSC expansion solution that includes the UM171 molecule and a Fed-batch HSC expansion system both of which combined have had major impact on CB transplantation. Indeed, to date more than 50 patients have received UM171/Fed-batch-expanded CB grafts with very promising results including low incidence of transplant-related mortality, chronic graft versus host disease and relapse rate. One of the key attributes of UM171/Fed-batch expanded CB is the inclusion of large numbers of immuno-modulatory cells, which we believe contribute to the success of these transplants. With the view of extending these attributes to bone marrow (BM) transplants, which are much more numerous than CB and hence further increasing the clinical impact of this procedure, we now propose three well-defined experimental aims:
First, we will develop a large-scale manufacturing process that will enable the production of UM171 expanded bone marrow grafts for our future clinical trial.
Second, considering our recent work showing that UM171 treatment of BM HSCs results in a marked increase in their ability to repopulate the thymus of humanized mice, we now intend to carefully characterize this important effect and verify if it is preserved in BM grafts derived from older donors which are typically associated with poor lymphoid function and clinical outcome. This will enable us to determine the optimal donor age in which this unique effect of UM171 is found and refine the design of our future clinical trial.
Third, we plan to characterize the cellular subpopulations in UM171-expanded BM grafts using state of the art technology, including CITE-Seq and preclinical functional assays. These essential preclinical studies will provide some understanding of the clinical impact of UM171 transplants and address regulatory issues associated with graft expansion.
These three aims represent an essential prerequisite of an optimal future clinical trial of UM171 bone marrow stem cell expansion whose final design will also be drafted using support and results from this grant.
1 September 2020
28 February 2022
2020
Guy Sauvageau (P)
Université de Montréal
Subventions de soutien à l’accélération de la transposition clinique
Sauvageau
Chercheur principal
Guy Sauvageau, Vincent-Philippe Lavallee
371 800
Bone marrow stem cell expansion with UM171: a better solution for patients and donors
Sang; leucémie
Hematopoietic stem cells (HSC) transplantation is one of the most effective therapeutic strategies for patients with hematological malignancies. Largely supported by the SCN, our group of collaborators developed a cord blood (CB)-derived HSC expansion solution that includes the UM171 molecule and a Fed-batch HSC expansion system both of which combined have had major impact on CB transplantation. Indeed, to date more than 50 patients have received UM171/Fed-batch-expanded CB grafts with very promising results including low incidence of transplant-related mortality, chronic graft versus host disease and relapse rate. One of the key attributes of UM171/Fed-batch expanded CB is the inclusion of large numbers of immuno-modulatory cells, which we believe contribute to the success of these transplants. With the view of extending these attributes to bone marrow (BM) transplants, which are much more numerous than CB and hence further increasing the clinical impact of this procedure, we now propose three well-defined experimental aims:
First, we will develop a large-scale manufacturing process that will enable the production of UM171 expanded bone marrow grafts for our future clinical trial.
Second, considering our recent work showing that UM171 treatment of BM HSCs results in a marked increase in their ability to repopulate the thymus of humanized mice, we now intend to carefully characterize this important effect and verify if it is preserved in BM grafts derived from older donors which are typically associated with poor lymphoid function and clinical outcome. This will enable us to determine the optimal donor age in which this unique effect of UM171 is found and refine the design of our future clinical trial.
Third, we plan to characterize the cellular subpopulations in UM171-expanded BM grafts using state of the art technology, including CITE-Seq and preclinical functional assays. These essential preclinical studies will provide some understanding of the clinical impact of UM171 transplants and address regulatory issues associated with graft expansion.
These three aims represent an essential prerequisite of an optimal future clinical trial of UM171 bone marrow stem cell expansion whose final design will also be drafted using support and results from this grant.
1 September 2020
28 February 2022
2020
Greg Korbutt (C)
University of Alberta
Subventions de soutien à l’accélération de la transposition clinique
Shapiro
Cochercheur
James Shapiro, Greg Korbutt
49 750
Autologous Patient-derived Islets from Induced Pluripotent Stem Cells (iPSC): The Next Generation Diabetes Therapy
Diabète
The University of Alberta under Dr. Shapiro’s direction has established a global presence as a leader in islet transplantation for T1D. Islet transplantation has a proven track record of success in effectively eradicating the risk of hypoglycemia while rendering many patients insulin free for variable periods. The downside, however, is the need for life-long immunosuppression, and a limited ability to isolate a full normal complement of islet mass to engraft in the recipient, as well as an insufficient organ donor pool requirement to meet the demand if indications for islet transplantation move beyond the select few with ‘brittle’ control. In contrast, human induced pluripotent stem cells (iPSCs) offer considerable promise as a renewable autologous β-cell source for transplantation without the need for chronic life-long immunosuppression. Human iPSC-derived β-cells have previously been shown to effectively control blood sugar and reverse diabetes in mice. In this proposal, we aim to validate human-derived autologous expanded iPSCs for generating β-like cells sourced from normal controls, patients with T1D, T2D and those with surgical diabetes after TP using established protocols, without the need for maintenance immune suppression. The purpose of using subjects with surgical diabetes, as controls, is to avoid potential initial challenges with either autoimmunity (in T1D) or insulin resistance (in T2D). The aim of the project is to evaluate iPSC-derived immature progenitor cells versus more mature functional β-like cells for scale-up. The ultimate goal is to establish GMP manufacturing processes to initiate a clinical trial for subcutaneous (phase 1 safety) followed by intraportal (phase 1/2 safety + efficacy) transplantation of autologous self-expanded β-like cells into TP patients, without immunosuppression, succeeded by transplantation in T2D and T1D patients.
The proposal shows strong potential for developing autologous cell therapy for the curative treatment of diabetes. Efforts to scale up GMP-grade iPSC-derived β-like cells will impart social benefit to Canadians and significantly relieve the current ever-increasing economic burden of diabetes healthcare in Canada. Our project team includes excellent researchers, clinicians and highly skilled technicians with stem cell expertise. In addition, we will collaborate with experts in islet regeneration, molecular genetics, transplant immunology, and GMP cell manufacturing.
1 September 2020
28 February 2022
2020
James Shapiro (P)
University of Alberta
Subventions de soutien à l’accélération de la transposition clinique
Shapiro
Chercheur principal
James Shapiro, Greg Korbutt
350 250
Autologous Patient-derived Islets from Induced Pluripotent Stem Cells (iPSC): The Next Generation Diabetes Therapy
Diabète
The University of Alberta under Dr. Shapiro’s direction has established a global presence as a leader in islet transplantation for T1D. Islet transplantation has a proven track record of success in effectively eradicating the risk of hypoglycemia while rendering many patients insulin free for variable periods. The downside, however, is the need for life-long immunosuppression, and a limited ability to isolate a full normal complement of islet mass to engraft in the recipient, as well as an insufficient organ donor pool requirement to meet the demand if indications for islet transplantation move beyond the select few with ‘brittle’ control. In contrast, human induced pluripotent stem cells (iPSCs) offer considerable promise as a renewable autologous β-cell source for transplantation without the need for chronic life-long immunosuppression. Human iPSC-derived β-cells have previously been shown to effectively control blood sugar and reverse diabetes in mice. In this proposal, we aim to validate human-derived autologous expanded iPSCs for generating β-like cells sourced from normal controls, patients with T1D, T2D and those with surgical diabetes after TP using established protocols, without the need for maintenance immune suppression. The purpose of using subjects with surgical diabetes, as controls, is to avoid potential initial challenges with either autoimmunity (in T1D) or insulin resistance (in T2D). The aim of the project is to evaluate iPSC-derived immature progenitor cells versus more mature functional β-like cells for scale-up. The ultimate goal is to establish GMP manufacturing processes to initiate a clinical trial for subcutaneous (phase 1 safety) followed by intraportal (phase 1/2 safety + efficacy) transplantation of autologous self-expanded β-like cells into TP patients, without immunosuppression, succeeded by transplantation in T2D and T1D patients.
The proposal shows strong potential for developing autologous cell therapy for the curative treatment of diabetes. Efforts to scale up GMP-grade iPSC-derived β-like cells will impart social benefit to Canadians and significantly relieve the current ever-increasing economic burden of diabetes healthcare in Canada. Our project team includes excellent researchers, clinicians and highly skilled technicians with stem cell expertise. In addition, we will collaborate with experts in islet regeneration, molecular genetics, transplant immunology, and GMP cell manufacturing.
1 September 2020
28 February 2022
2020
Glen Tibbits (P)
Simon Fraser University
Subventions de soutien à l’accélération de la transposition clinique
Tibbits
Chercheur principal
Glen Tibbits, Francis Lynn, Shubhayan Sanatani, Filip van Petegem
217 415
Developing a hiPSC-CM based model for personalized treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT)
Cardiaque
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Francis Lynn (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Tibbits
Cochercheur
Glen Tibbits, Francis Lynn, Shubhayan Sanatani, Filip van Petegem
33 210
Developing a hiPSC-CM based model for personalized treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT)
Cardiaque
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Shubhayan Sanatani (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Tibbits
Cochercheur
Glen Tibbits, Francis Lynn, Shubhayan Sanatani, Filip van Petegem
51 450
Developing a hiPSC-CM based model for personalized treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT)
Cardiaque
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Filip van Petegem (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Tibbits
Cochercheur
Glen Tibbits, Francis Lynn, Shubhayan Sanatani, Filip van Petegem
97 875
Developing a hiPSC-CM based model for personalized treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT)
Cardiaque
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Paul Frankland (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 333
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
David Kaplan (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 333
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Donald Mabbott (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
25 000
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Freda Miller (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 333
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Cindi Morshead (C)
University of Toronto
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 333
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Douglas Munoz (C)
Queen's University
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
25 000
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Jiwon Oh (C)
University of Toronto
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
5 000
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Jing Wang (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 332
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Ann Yeh (P)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Chercheur principal
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
25 000
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Neural, neuronal, neurale, neuronale, neurales, neuronales; sclérose en plaques
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Wolfram Tetzlaff (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Yeh
Cochercheur
Ann Yeh, Jing Wang, Jiwon Oh, Douglas Munoz, Cindi Morshead, Freda Miller, Donald Mabbott, David Kaplan, Paul Frankland, Wolfram Tetzlaff
53 333
Pharmacological recruitment of endogenous neural precursors to promote white matter repair in MS
Damage to brain white matter, which contains myelinated axons, occurs following injury and in disorders like multiple sclerosis, and results in sensory, motor, and cognitive problems. Currently, there are no effective medical therapies to promote brain repair and reduce disability following white matter damage. In this proposal, we hope to change this situation by enhancing the genesis of new oligodendrocytes, the cells that make myelin, and in so doing to promote white matter repair. To do this, we will take advantage of the fact that our brains contain resident neural precursor cells (NPCs) that normally make oligodendrocytes throughout life, and will ask whether we can pharmacologically activate these endogenous NPCs to promote repair. Excitingly, our team has discovered that a widely-used and safe drug, metformin, will enhance the genesis of oligodendrocytes from NPCs and that, following pediatric neural injury, this promotes neuroanatomical and functional recovery. In this proposal, we will translate this finding to the clinic, with the ultimate goal of a clinical trial for metformin in children and adolescents with white matter damage. To attain this goal, we will perform preclinical work in different mouse models of white matter damage, asking whether metformin can enhance brain function as it promotes white matter repair. At the same time, we will develop outcome measures that will allow us to measure the efficacy of metformin in children and adolescents with white matter damage. Finally, we will search for additional methods of activating brain stem cells so that they make more oligodendrocytes, with the idea that ultimately we will use combinatorial approaches to treat white matter damage in humans. To pursue these objectives, we have assembled an expert team including both basic scientists (Cindi Morshead, Jing Wang, Paul Frankland, Freda Miller, Wolfram Tetzlaff, David Kaplan and Doug Munoz) and clinician-scientists (Ann Yeh and Don Mabbott). If we obtain positive results in our clinical trial, then this will lead to a dramatic shift in how we treat children/teenagers with white matter injury. In addition, this work will pave the way for future additional clinical trials in children and adults with white matter damage as a consequence of multiple sclerosis, stroke, traumatic brain injury, spinal cord injury and cerebral palsy.
1 September 2020
28 February 2022
2020
Jonas Mattsson (C)
University Health Network
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Cochercheur
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
80 000
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTImm)
Sang
Current standard cancer treatments for patients receiving hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most subsets of immune cells
recover quickly, T-cells, which are key components of the immune system, remain absent or at low levels for many months to years, especially in the elderly. This increases susceptibility to cancer relapse and opportunistic infections. To help control these adverse effects lengthy treatment with antibiotics and antivirals, and in some cases an infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease that in serious cases can lead to organ failure and death. Therefore, complications as a result of lack of T-cells or presence of donor T-cells can very adversely affect patients’ health.
To provide these patients with a much-needed T-cell boost, using our innovative DL4-μbead approach, we can now generate progenitor T-cells from donor blood stem cells in culture. This
method will help speed replenishment of T-cells in post-transplant patients as infused progenitor T-cells will seed the thymus of patient, where they develop into mature T cells. Progenitor T-cells also have the effect of repairing thymus after its injury due to chemo/radiation treatment. Importantly, apart from conferring immunity, the emerging T-cell would also be tolerant to host and would not cause graft-versus-host disease. Preclinical studies in animal models have demonstrated that this is an effective and potentially curative treatment. Hence, progenitor T-cells would likely improve the quality of life of HSCT patients by decreasing their susceptibility to deadly infections and relapse.
In short, our novel method possesses an enormous potential to not only improve the immune function but also to transform the field of hematopoietic transplantation in that: 1) proT cells will reduce mortality and disease leading to decreased instances of hospitalization; 2) it will reduce the current need for BM-derived HSC donations by directly increasing the number of proT cells precursors; and 3) it will permit the establishment of personalized immunotherapy through genetic manipulation of proT cells. These innovative outcomes will transform how immunereconstitution is achieved in cancer patients.
1 September 2020
28 February 2022
2020
Donna Wall (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Cochercheur
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
80 000
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTImm)
Sang
Current standard cancer treatments for patients receiving hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most subsets of immune cells
recover quickly, T-cells, which are key components of the immune system, remain absent or at low levels for many months to years, especially in the elderly. This increases susceptibility to cancer relapse and opportunistic infections. To help control these adverse effects lengthy treatment with antibiotics and antivirals, and in some cases an infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease that in serious cases can lead to organ failure and death. Therefore, complications as a result of lack of T-cells or presence of donor T-cells can very adversely affect patients’ health.
To provide these patients with a much-needed T-cell boost, using our innovative DL4-μbead approach, we can now generate progenitor T-cells from donor blood stem cells in culture. This
method will help speed replenishment of T-cells in post-transplant patients as infused progenitor T-cells will seed the thymus of patient, where they develop into mature T cells. Progenitor T-cells also have the effect of repairing thymus after its injury due to chemo/radiation treatment. Importantly, apart from conferring immunity, the emerging T-cell would also be tolerant to host and would not cause graft-versus-host disease. Preclinical studies in animal models have demonstrated that this is an effective and potentially curative treatment. Hence, progenitor T-cells would likely improve the quality of life of HSCT patients by decreasing their susceptibility to deadly infections and relapse.
In short, our novel method possesses an enormous potential to not only improve the immune function but also to transform the field of hematopoietic transplantation in that: 1) proT cells will reduce mortality and disease leading to decreased instances of hospitalization; 2) it will reduce the current need for BM-derived HSC donations by directly increasing the number of proT cells precursors; and 3) it will permit the establishment of personalized immunotherapy through genetic manipulation of proT cells. These innovative outcomes will transform how immunereconstitution is achieved in cancer patients.
1 September 2020
28 February 2022
2020
Juan Carlos Zúñiga-Pflücker (P)
Sunnybrook Research Institute
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Chercheur principal
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
240 000
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTImm)
Sang; immunothérapie pour le cancer, immunothérapies
Current standard cancer treatments for patients receiving hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most subsets of immune cells
recover quickly, T-cells, which are key components of the immune system, remain absent or at low levels for many months to years, especially in the elderly. This increases susceptibility to cancer relapse and opportunistic infections. To help control these adverse effects lengthy treatment with antibiotics and antivirals, and in some cases an infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease that in serious cases can lead to organ failure and death. Therefore, complications as a result of lack of T-cells or presence of donor T-cells can very adversely affect patients’ health.
To provide these patients with a much-needed T-cell boost, using our innovative DL4-μbead approach, we can now generate progenitor T-cells from donor blood stem cells in culture. This
method will help speed replenishment of T-cells in post-transplant patients as infused progenitor T-cells will seed the thymus of patient, where they develop into mature T cells. Progenitor T-cells also have the effect of repairing thymus after its injury due to chemo/radiation treatment. Importantly, apart from conferring immunity, the emerging T-cell would also be tolerant to host and would not cause graft-versus-host disease. Preclinical studies in animal models have demonstrated that this is an effective and potentially curative treatment. Hence, progenitor T-cells would likely improve the quality of life of HSCT patients by decreasing their susceptibility to deadly infections and relapse.
In short, our novel method possesses an enormous potential to not only improve the immune function but also to transform the field of hematopoietic transplantation in that: 1) proT cells will reduce mortality and disease leading to decreased instances of hospitalization; 2) it will reduce the current need for BM-derived HSC donations by directly increasing the number of proT cells precursors; and 3) it will permit the establishment of personalized immunotherapy through genetic manipulation of proT cells. These innovative outcomes will transform how immunereconstitution is achieved in cancer patients.
1 September 2020
28 February 2022
2020
Manuel Caruso (C)
Université Laval
Subventions de soutien à l’accélération de la transposition clinique
Germain
Cochercheur
Lucie Germain, Elena Pope, Bartha Knoppers, Manuel Caruso
12 000
Towards an epidermolysis bullosa clinical trial with tissue-engineered skin after ex vivo gene therapy correction
Peau
Rare disease status
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease affecting the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for EB. The only option is to treat the recurrent wounds with daily care and bandages. Patients experience pain, suffering and poor quality of life.
The LOEX/CHU de Québec-Université Laval, a leader in the autologous self-assembled skin substitute (SASS) therapy, using cultured stem cells for the treatment of burn patients, has initiated research studies to find a cure for RDEB. Our interdisciplinary team brings together: two fundamental investigators, including an expert in stem cells and tissue engineering and a specialist in gene therapy, an expert in socio-ethical and legal issues, a pediatric dermatologist, the medical director of the largest Canadian EB clinic and many research professionals experienced in the clinical translation of tissue engineering products. Thus, our infrastructure, expertise and knowledge will ensure the success of this project.
The objective of the present proposal is to complete the steps necessary for the translation, from the laboratory to the clinic, of our new therapeutic approach combining gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce self-assembled skin substitutes from autologous RDEB cells previously corrected in vitro by gene therapy (GMEB-SASSs). This proposal aims to perform pre-clinical testing in vitro and in vivo for the gene-modified SASS. We will also prepare the necessary documentation to undertake a clinical trial evaluating the treatment safety and efficacy for RDEB.
Ultimately, our goal is to develop a definitive treatment for RDEB. Without a cure, RDEB patients have recurrent wounds. The annual costs for specialized bandages is very expensive. This rare disease impacts on the quality of life of patients and their families. Therefore, this new treatment, if proven successful, could change lives of Canadian patients by improving skin stability and preventing recurring wounds.
1 September 2020
28 February 2022
2020
Bartha Knoppers (C)
Université McGill
Subventions de soutien à l’accélération de la transposition clinique
Germain
Cochercheur
Lucie Germain, Elena Pope, Bartha Knoppers, Manuel Caruso
30 000
Towards an epidermolysis bullosa clinical trial with tissue-engineered skin after ex vivo gene therapy correction
Peau
Rare disease status
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease affecting the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for EB. The only option is to treat the recurrent wounds with daily care and bandages. Patients experience pain, suffering and poor quality of life.
The LOEX/CHU de Québec-Université Laval, a leader in the autologous self-assembled skin substitute (SASS) therapy, using cultured stem cells for the treatment of burn patients, has initiated research studies to find a cure for RDEB. Our interdisciplinary team brings together: two fundamental investigators, including an expert in stem cells and tissue engineering and a specialist in gene therapy, an expert in socio-ethical and legal issues, a pediatric dermatologist, the medical director of the largest Canadian EB clinic and many research professionals experienced in the clinical translation of tissue engineering products. Thus, our infrastructure, expertise and knowledge will ensure the success of this project.
The objective of the present proposal is to complete the steps necessary for the translation, from the laboratory to the clinic, of our new therapeutic approach combining gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce self-assembled skin substitutes from autologous RDEB cells previously corrected in vitro by gene therapy (GMEB-SASSs). This proposal aims to perform pre-clinical testing in vitro and in vivo for the gene-modified SASS. We will also prepare the necessary documentation to undertake a clinical trial evaluating the treatment safety and efficacy for RDEB.
Ultimately, our goal is to develop a definitive treatment for RDEB. Without a cure, RDEB patients have recurrent wounds. The annual costs for specialized bandages is very expensive. This rare disease impacts on the quality of life of patients and their families. Therefore, this new treatment, if proven successful, could change lives of Canadian patients by improving skin stability and preventing recurring wounds.
1 September 2020
28 February 2022
2020
Elena Pope (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Germain
Cochercheur
Lucie Germain, Elena Pope, Bartha Knoppers, Manuel Caruso
6 000
Towards an epidermolysis bullosa clinical trial with tissue-engineered skin after ex vivo gene therapy correction
Peau
Rare disease status
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease affecting the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for EB. The only option is to treat the recurrent wounds with daily care and bandages. Patients experience pain, suffering and poor quality of life.
The LOEX/CHU de Québec-Université Laval, a leader in the autologous self-assembled skin substitute (SASS) therapy, using cultured stem cells for the treatment of burn patients, has initiated research studies to find a cure for RDEB. Our interdisciplinary team brings together: two fundamental investigators, including an expert in stem cells and tissue engineering and a specialist in gene therapy, an expert in socio-ethical and legal issues, a pediatric dermatologist, the medical director of the largest Canadian EB clinic and many research professionals experienced in the clinical translation of tissue engineering products. Thus, our infrastructure, expertise and knowledge will ensure the success of this project.
The objective of the present proposal is to complete the steps necessary for the translation, from the laboratory to the clinic, of our new therapeutic approach combining gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce self-assembled skin substitutes from autologous RDEB cells previously corrected in vitro by gene therapy (GMEB-SASSs). This proposal aims to perform pre-clinical testing in vitro and in vivo for the gene-modified SASS. We will also prepare the necessary documentation to undertake a clinical trial evaluating the treatment safety and efficacy for RDEB.
Ultimately, our goal is to develop a definitive treatment for RDEB. Without a cure, RDEB patients have recurrent wounds. The annual costs for specialized bandages is very expensive. This rare disease impacts on the quality of life of patients and their families. Therefore, this new treatment, if proven successful, could change lives of Canadian patients by improving skin stability and preventing recurring wounds.
1 September 2020
28 February 2022
2020
Lucie Germain (P)
Université Laval
Subventions de soutien à l’accélération de la transposition clinique
Germain
Chercheur principal
Lucie Germain, Elena Pope, Bartha Knoppers, Manuel Caruso
352 000
Towards an epidermolysis bullosa clinical trial with tissue-engineered skin after ex vivo gene therapy correction
Peau; épidermolyse bulleuse
Rare disease status
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease affecting the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for EB. The only option is to treat the recurrent wounds with daily care and bandages. Patients experience pain, suffering and poor quality of life.
The LOEX/CHU de Québec-Université Laval, a leader in the autologous self-assembled skin substitute (SASS) therapy, using cultured stem cells for the treatment of burn patients, has initiated research studies to find a cure for RDEB. Our interdisciplinary team brings together: two fundamental investigators, including an expert in stem cells and tissue engineering and a specialist in gene therapy, an expert in socio-ethical and legal issues, a pediatric dermatologist, the medical director of the largest Canadian EB clinic and many research professionals experienced in the clinical translation of tissue engineering products. Thus, our infrastructure, expertise and knowledge will ensure the success of this project.
The objective of the present proposal is to complete the steps necessary for the translation, from the laboratory to the clinic, of our new therapeutic approach combining gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce self-assembled skin substitutes from autologous RDEB cells previously corrected in vitro by gene therapy (GMEB-SASSs). This proposal aims to perform pre-clinical testing in vitro and in vivo for the gene-modified SASS. We will also prepare the necessary documentation to undertake a clinical trial evaluating the treatment safety and efficacy for RDEB.
Ultimately, our goal is to develop a definitive treatment for RDEB. Without a cure, RDEB patients have recurrent wounds. The annual costs for specialized bandages is very expensive. This rare disease impacts on the quality of life of patients and their families. Therefore, this new treatment, if proven successful, could change lives of Canadian patients by improving skin stability and preventing recurring wounds.
1 September 2020
28 February 2022
2020
Sandra Cohen (P)
Hôpital Maisonneuve-Rosemont
Avancement des essais cliniques
Cohen
Chercheur principal
Sandra Cohen
1 600 000
UM171-Expanded Cord Blood Grafts Offer Potential Cure for Very High-Risk Leukemia Patients
Sang; leucémie
Stem cell transplantation is one of the best therapies to cure blood cancers. Unfortunately, the risks of relapse (≈30%) and of dying from complications related to the transplant (also known as transplant related mortality ≈20%) remain high. Usually, patients receive bone marrow or blood stem cells from a related or unrelated compatible donor. Cord blood (CB) is an attractive alternative stem cell source due to its unique properties, including low risk of chronic graft-versus-host disease (GVHD) and relapse. A lower risk of chronic GVHD is very important as it is the major determinant of long-term quality of life after a transplant. However, these advantages of CB transplants are offset by the limited cell dose (i.e. small cords), which results in delayed recovery of blood counts, increased infections, prolonged hospitalization and early mortality. We have now completed a first clinical trial to test 2 Canadian discoveries, the UM171 small molecule developed in G. Sauvageau and A. Marinier’s laboratories (University of Montreal) and an optimized culture system from P. Zandstra’s laboratory (University of British Columbia). Combined, these ground-breaking technologies increase the number of stem cells in CB and were able to dramatically reduce transplant related mortality (<5%) with a very low risk of chronic GVHD. Most relevant to this grant, we also noticed a very low risk of blood cancer relapse in patients who had diseases with a very high risk of recurrence.
We now seek financial support to treat patients in a new trial to confirm that indeed UM171 CB has a potent anti-leukemia effect. For this we propose to recruit 20 very high risk acute leukemia/preleukemia patients (expected cure rate with standard transplant ≈20%) and compare them to historical control patients transplanted with similar high-risk disease. For this, we have brought together a Canadian multidisciplinary team with state-of-the-art expertise in stem cell biology, immunology, bioengineering, cell therapy, statistics and clinical transplantation. Using UM171-expanded CB grafts, we expect a cure rate of at least 50%, more than doubling the current expected results. This could represent a real breakthrough treatment for these mostly uncurable patients.
1 January 2020
31 January 2022
2020
Veronique Moulin (P)
Université Laval
Avancement des essais cliniques
Moulin
Chercheur principal
Veronique Moulin
670 645
Self-Assembly Skin Substitutes (SASS) for the treatment of acute wounds of Canadian burn patients
Brûlure cutanée, brûlures cutanées, brûlures de la peau
The treatment of burn wounds is based on skin autografts. When the surface that needs to be covered is superior to 50% of the total body surface area, the treatment with autografts becomes strategic, the extent of the burns reducing the donor sites availability. With the tissue engineering method developed in our lab, autologous Self-Assembly Skin Substitutes (SASS) can be produced from only a small skin biopsy and could permanently cover all the patient wounds. Thanks to the Special Access Program of Health Canada, 14 patients have already been treated with very good results. This early phase clinical trial has now been accepted by Health Canada and few patients have been treated in Quebec Province. This project will allow to extend the trial to burn units in the rest of Canada. The aim of this trial is to evaluate this novel therapeutic approach, treating 17 patients to help skin regeneration. We plan to recruit at least 7 patients during the 2 next years and evaluate graft take and the post-grafting scar aspect during 2 to 3 years. Our aim is to treat majority of Canadian patients that have been burned on more than 50% of their body during the 2 years to come. To reach this goal, we will collaborate with the Canadian surgeons that are dedicated to the burn patient treatment. We speculate that SASS treatment will have economic and social benefits as our preliminary results have demonstrated that treatment decreases the morbidity generated by the standard treatment (decreasing further surgery needs and pain of the patients) and improves the quality of the post-burn scars.
Our interdisciplinary team is composed of four internationally known researchers in regenerative medicine from two universities and of plastic surgeons working in the major Canadian burn unit sites. Manufacturing SASS in Tissue processing centre built and directed by our team, we are the only Canadian team dedicated to the reconstruction of organized tissues to treat patients. At the end of the clinical trial and acceptance by Health Canada, we will be the first place in Canada to routinely treat patients with autologous reconstructed skin.
1 January 2020
31 January 2022
2020
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Avancement des essais cliniques
Thébaud
Chercheur principal
Bernard Thébaud
638 150
HULC-I: Helping Underdeveloped Lungs with mesenchymal stromal Cells – A phase I trial
Poumon, poumons
Extreme prematurity is the main cause of death in children below 5 years of age. The most severe complication is bronchopulmonary dysplasia (BPD), a chronic lung disease that follows ventilator and oxygen treatment for acute failure to breathe. BPD also leads to brain damage and blindness. Currently, there is no treatment for BPD. Because these injuries occur in developing organs, consequences are life-long and carry a high economic burden. Thus, effective interventions at this stage of life provide exceptional value.
Our group was the first to demonstrate that umbilical cord-derived mesenchymal stromal cells (uc-MSCs) repair neonatal lung injury in experimental models. We then pioneered several innovations enabling this world’s first clinical trial: (1) a highly efficient, high yield, low passage, GMP clinical-grade uc-MSC product; (2) a novel team science approach (INCuBATOR: Innovative-Neonatal-CellUlar-therapies-for-BPD-Accelerating-Translation-Of-Research) to enhance clinical translation success through rigorous, evidence-based processes mitigating the potential high-risk nature of cell therapy in newborns. Thus, we created a strong, multidisciplinary, well-attuned, international team with complementary expertise to deliver on this research.
HULC-I is a Phase I, dose-escalation trial to determine the safety and feasibility of intravenous injection of allogeneic uc-MSCs for extreme preterm infants at high risk of developing BPD. The study includes an observational control group (n=12) and an interventional group (n=9). Our multi-disciplinary team has extensive experience in stem cell biology/manufacturing, clinical trials, health psychology and economics to ensure the success of this trial. The deliverables are to provide evidence for a larger, Phase II Canadian multi-centre trial, to determine the safety and efficacy of uc-MSCs. Ultimately, HULC-I will provide a potential breakthrough therapy to improve the outcome of extreme preterm babies in Canada and world-wide.
HULC-I will also deliver social and economic benefits by providing a new workforce of HQP and developing novel commercial entities. Our partner at the Technische Universität Dresden holds a patent for the uc-MSC product that is currently being internationalized in Europe, USA and Canada. The spin-off MDTB Cells GmbH will further develop and distribute a novel, high quality uc-derived MSC product with plans to establish a spin-off in Canada to facilitate operations in North America.
1 January 2020
31 January 2022
2020
Lucie Germain (P)
Université Laval
Avancement des essais cliniques
Germain
Chercheur principal
Lucie Germain
500 000
Cultured epithelial corneal autografts for the treatment of Canadians with limbal stem cell deficiency
Oculaire, déficit en cellules souches limbiques
Limbal stem cell deficiency (LSCD) is a severe disease caused by damage or depletion of stem cells in the corneal limbal region of the eye following trauma or disease. The LOEX/CHU de Québec, a leader in autologous epithelium therapy using cultured stem cells, has performed the first clinical trial in Canada offering cultured epithelial corneal autograft (CECA) as a treatment for the LSCD.
The objective of the present proposal is to develop a multicenter clinical trial (Quebec, Montreal and Toronto) to recruit a greater number of LSCD patients for the collection of safety data on the CECA graft, but with a primary endpoint focused on efficacy. Therefore, we expect to: i) establish and organize new clinical sites, which involves the training of new cornea specialists for CECA grafting, ii) recruit and treat 34 adult patients and 5 minor patients, and iii) educate and advise Canadian ophthalmologists on this new therapeutic alternative now available in Canada.
Following successful clinical testing, this trial will provide clinical proof-of-concept for a safe and effective stem cell-based therapy accessible to Canadian ophthalmologists and their patients for the treatment of LSCD. Without treatment, LSCD results in severe visual impairments which impacts on the quality of life of patients and their families. LSCD is a rare disease that affects patients' ability of the patient to work, drive and conduct their daily activities. Therefore, this new treatment, if proven successful, could change lives of Canadian patients by improving vision in their affected eye.
Our interdisciplinary team brings together three fundamental investigators, including two experts in tissue-engineering and an expert in ethical/legal issues, three clinician ophtalmologists, one pathologist, many research professionals experienced in the clinical translation of tissue engineering products and a patient representative. The LOEX is equipped with clean rooms and has been producing CECA since 2012. Thus, our research group has the infrastructure, expertise and knowledge to ensure the success of the project.
1 January 2020
31 January 2022
2020
Yun Li (C)
Hospital for Sick Children
L’intervention de recherche rapide du RCS contre la COVID-19
Muffat
Cochercheur
Yun Li, Julien Muffat
90 000
Investigating the role of inflammatory responses in neurological effects of COVID-19, using patient-derived stem cell models
COVID-19, neural, neuronale
The COVID-19 pandemic, due to the coronavirus SARS-CoV-2, is taking an enormous toll on populations worldwide. The primary presentation is pneumonia, yet the disease clearly affects multiple organs, often culminating in liver and kidney damage. Severity of the disease may often find its roots in an inappropriately intense and prolonged innate immune response, a so-called cytokine storm, driven by innate immune cells (macrophages). Strikingly, many patients report sensory symptoms, such as loss of smell and taste, pains, visual disturbances, and headaches. These indicate that the virus may target the brain. The brain harbors a population of prototypic tissue-resident innate immune cells, the microglia. In the brain, these cells are normally protected from peripheral insults. However, they will respond to inflammatory stimuli that do reach them, and are known to be the target of neuro-invasive viruses. We propose to investigate the neuro-invasive potential of SARS-CoV-2, with an emphasis on the role of resident innate immune cells in mediating the injury. Given the species restriction of SARS-CoV-2, we will work with a set of novel human tissue culture models that we uniquely developed to investigate inflammatory etiologies of neurological diseases. We previously successfully and rapidly deployed similar technologies during the Zika epidemic. We will assess infection parameters and cellular responses in brain cells derived from patient stem cells. Working with brain-resident immune cells will shed light on the interaction of SARS-CoV-2 with similar cellular targets in other organs, such as the lungs. We will study the virus’ ability to enter, replicate, kill the cells or trigger unchecked inflammation. We will dissect the host machinery involved in these responses by identifying protective or damaging mutations, generated using CRISPR technology for every gene in those cells. Our team has the technical know-how and access to all resources needed to deliver rapidly on our plans.
17 April 2020
16 April 2021
2020
Julien Muffat (P)
Hospital for Sick Children
L’intervention de recherche rapide du RCS contre la COVID-19
Muffat
Chercheur principal
Yun Li, Julien Muffat
90 000
Investigating the role of inflammatory responses in neurological effects of COVID-19, using patient-derived stem cell models
COVID-19, neural, neuronale
The COVID-19 pandemic, due to the coronavirus SARS-CoV-2, is taking an enormous toll on populations worldwide. The primary presentation is pneumonia, yet the disease clearly affects multiple organs, often culminating in liver and kidney damage. Severity of the disease may often find its roots in an inappropriately intense and prolonged innate immune response, a so-called cytokine storm, driven by innate immune cells (macrophages). Strikingly, many patients report sensory symptoms, such as loss of smell and taste, pains, visual disturbances, and headaches. These indicate that the virus may target the brain. The brain harbors a population of prototypic tissue-resident innate immune cells, the microglia. In the brain, these cells are normally protected from peripheral insults. However, they will respond to inflammatory stimuli that do reach them, and are known to be the target of neuro-invasive viruses. We propose to investigate the neuro-invasive potential of SARS-CoV-2, with an emphasis on the role of resident innate immune cells in mediating the injury. Given the species restriction of SARS-CoV-2, we will work with a set of novel human tissue culture models that we uniquely developed to investigate inflammatory etiologies of neurological diseases. We previously successfully and rapidly deployed similar technologies during the Zika epidemic. We will assess infection parameters and cellular responses in brain cells derived from patient stem cells. Working with brain-resident immune cells will shed light on the interaction of SARS-CoV-2 with similar cellular targets in other organs, such as the lungs. We will study the virus’ ability to enter, replicate, kill the cells or trigger unchecked inflammation. We will dissect the host machinery involved in these responses by identifying protective or damaging mutations, generated using CRISPR technology for every gene in those cells. Our team has the technical know-how and access to all resources needed to deliver rapidly on our plans.
17 April 2020
16 April 2021
2020
Amy Wong (C)
Hospital for Sick Children
L’intervention de recherche rapide du RCS contre la COVID-19
Stanford
Cochercheur
William Stanford, Amy Wong
77 120
Identifying and targeting pulmonary and immune mechanisms in COVID-19 using human stem cell derived lineages
COVID-19, poumon, poumons, pulmonaire, vasculaire
Understanding why some COVID-19 patients develop acute respiratory distress syndrome (ARDS) that drives morbidity and mortality is unclear but is urgently needed to determine which patients should be treated early and develop therapeutic interventions to save lives. The two known comorbidities – hypertension and diabetes – associated with severe COVID-19 suggests a vascular pathology. In fact, in addition to the respiratory epithelia, the lung vasculature expresses high levels of angiotensin converting enzyme-2 (ACE-2), the receptor that SARS-CoV-2 uses to infect cells. Additionally, it appears from emerging studies that a myeloid-dominant cytokine storm contributes to lung tissue injury in COVID-19 ARDS.
With our partners at BioSymetrics, we will leverage our team’s expertise in lung and stem cell biology, disease modeling, immunology, bioengineering, drug screening and development, and infectious disease to dissect underlying molecular and cellular mechanisms driving disease severity and screen for disease modifying drugs. To maximize translational impact, our team’s unique approach uses human pluripotent stem cells to generate ACE2-expressing respiratory epithelia grown in a tissue-mimetic air liquid interface and vascular cells grown in a lung-mimetic hydrogel to analyze infectivity and cellular and molecular behaviour in response to SARS-CoV-2. Moreover, we will perform single cell RNA-seq analyses and co-culture studies with control and infected peripheral blood derived myeloid cells to model the altered lung epithelia, vascular, and immune responses in COVID-19. These mechanistic studies will be mined to discover putative biomarkers that identify patients likely to require intensive care so that acute care may be started early to prevent the need for intensive care. Finally, using a novel ACE2 activity high content imaging assay, we will implement a Health Canada/FDA approved drug repurposing screen to identify therapeutics to reduce disease severity.
17 April 2020
16 April 2021
2020
William Stanford (P)
L'Institut de recherche de l'Hôpital d'Ottawa
L’intervention de recherche rapide du RCS contre la COVID-19
Stanford
Chercheur principal
William Stanford, Amy Wong
118 750
Identifying and targeting pulmonary and immune mechanisms in COVID-19 using human stem cell derived lineages
COVID-19, poumon, poumons, pulmonaire, vasculaire
Understanding why some COVID-19 patients develop acute respiratory distress syndrome (ARDS) that drives morbidity and mortality is unclear but is urgently needed to determine which patients should be treated early and develop therapeutic interventions to save lives. The two known comorbidities – hypertension and diabetes – associated with severe COVID-19 suggests a vascular pathology. In fact, in addition to the respiratory epithelia, the lung vasculature expresses high levels of angiotensin converting enzyme-2 (ACE-2), the receptor that SARS-CoV-2 uses to infect cells. Additionally, it appears from emerging studies that a myeloid-dominant cytokine storm contributes to lung tissue injury in COVID-19 ARDS.
With our partners at BioSymetrics, we will leverage our team’s expertise in lung and stem cell biology, disease modeling, immunology, bioengineering, drug screening and development, and infectious disease to dissect underlying molecular and cellular mechanisms driving disease severity and screen for disease modifying drugs. To maximize translational impact, our team’s unique approach uses human pluripotent stem cells to generate ACE2-expressing respiratory epithelia grown in a tissue-mimetic air liquid interface and vascular cells grown in a lung-mimetic hydrogel to analyze infectivity and cellular and molecular behaviour in response to SARS-CoV-2. Moreover, we will perform single cell RNA-seq analyses and co-culture studies with control and infected peripheral blood derived myeloid cells to model the altered lung epithelia, vascular, and immune responses in COVID-19. These mechanistic studies will be mined to discover putative biomarkers that identify patients likely to require intensive care so that acute care may be started early to prevent the need for intensive care. Finally, using a novel ACE2 activity high content imaging assay, we will implement a Health Canada/FDA approved drug repurposing screen to identify therapeutics to reduce disease severity.
17 April 2020
16 April 2021
2020
Duncan Stewart (P)
L'Institut de recherche de l'Hôpital d'Ottawa
L’intervention de recherche rapide du RCS contre la COVID-19
Stewart
Chercheur principal
Duncan Stewart
300 000
Cellular Immuno-Therapy for COVID-19 induced Acute Respiratory Distress Syndrome: the CIRCA-19 Trial
The clinical picture of the novel corona virus 2 (SARS-CoV-2) disease (COVID-19) is rapidly evolving. Although 80% of infections may be mild, up to 25% of all patients admitted to hospital require admission to the intensive care unit, and as many as 40% will progress to develop severe problems breathing due to the acute respiratory distress syndrome (ARDS). This often requires mechanical ventilation, with a 50% risk of mortality. Researchers at the Ottawa Hospital Research Institute (OHRI) have been studying the potential therapeutic role of mesenchymal stromal/stem cells, or MSCs, for the treatment of ARDS for over a decade. This has led to the world’s first clinical trial using MSC therapy for patients with severe infections (sepsis) which often are associated with ARDS. This trial demonstrated tolerability, and some signs of efficacy. In addition, we have established expertise in producing clinical-grade MSCs and have received approval from Health Canada for the use of MSCs in 3 different clinical studies. Here, we propose a series of trials to allow us to rapidly initiate a clinical study to establish feasibility and safety of MSCs treatment in patients with COVID-19 related ARDS. In total, 27 patients will be entered into three sequential trial. The first trial, called the ‘Vanguard’ study, is designed to determine the optimal of dose of bone marrow-derived MSCs to be used for these very sick patients. The next two trials will use this same optimal dose of cells, but will administer MSCs derived from the umbilical cord, which is an abundant and readily available source. In this way we will confirm the safety of the use of umbilical cord MSCs and obtain preliminary information about their potential benefits in the treatment of this often lethal disease.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
Targeting Endogenous Repair: A Novel Mutation Independent Pharmacological Approach for the Treatment of Muscular Dystrophy
Muscle, muscles
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
1 January 2020
31 January 2022
2020
Jodi Warman (C)
Université d’Ottawa
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Khacho
Cochercheur
Mireille Khacho, Jodi Warman
20 300
Mitochondrial dynamics as a therapeutic target for muscle stem cells in muscle wasting diseases
Muscle, muscles
Rare disease status
An estimated 4 million Canadians currently suffer from muscle wasting conditions, manifesting as loss of muscle mass and function. Muscle wasting is the most significant cause of disability in the aging population and individuals with muscle degenerative diseases, including muscular dystrophies, myopathies and aging. The decline in muscle function affects mobility, voluntary function and quality of life, often leading to institutionalization and mortality. This imposes a dramatic burden on individuals and society, costing Canadians several billions of dollars per year. Thus, there is a pressing need for the development of preventative and therapeutic strategies targeting muscle wasting. For many years, muscle wasting was thought to be only a problem of the myofibers, yet recent evidence shows that muscle stem cell (MuSC) dysfunction plays a significant role. Adult skeletal muscle normally has a high regenerative capacity, however, within the context of muscle wasting MuSCs are depleted and muscle regeneration is impaired. Currently, the reason for MuSC depletion is unclear and thus there are no therapies targeting their restoration. Understanding the underlying etiological factors leading to MuSC depletion is instrumental in identifying novel approaches to restore muscle repair and function. Our recent studies were the first to uncovered that dysregulation of mitochondrial dynamics and function, as observed in muscle wasting, impairs stem cell longevity and regenerative capacity. The overarching goal of this proposal is to restore MuSC number and function and promote muscle repair in aging and muscle wasting diseases. The combination of our proposed animal and human studies of muscle stem cells will provide novel therapeutic options using pharmaceutical and supplementation strategies. Importantly, this could have immediate translational potential to a clinical environment to improve muscle function and quality of life in patients.
1 September 2020
28 February 2022
2020
Mireille Khacho (P)
Université d’Ottawa
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Khacho
Chercheur principal
Mireille Khacho, Jodi Warman
129 700
Mitochondrial dynamics as a therapeutic target for muscle stem cells in muscle wasting diseases
Muscle, muscles; divers
Rare disease status
An estimated 4 million Canadians currently suffer from muscle wasting conditions, manifesting as loss of muscle mass and function. Muscle wasting is the most significant cause of disability in the aging population and individuals with muscle degenerative diseases, including muscular dystrophies, myopathies and aging. The decline in muscle function affects mobility, voluntary function and quality of life, often leading to institutionalization and mortality. This imposes a dramatic burden on individuals and society, costing Canadians several billions of dollars per year. Thus, there is a pressing need for the development of preventative and therapeutic strategies targeting muscle wasting. For many years, muscle wasting was thought to be only a problem of the myofibers, yet recent evidence shows that muscle stem cell (MuSC) dysfunction plays a significant role. Adult skeletal muscle normally has a high regenerative capacity, however, within the context of muscle wasting MuSCs are depleted and muscle regeneration is impaired. Currently, the reason for MuSC depletion is unclear and thus there are no therapies targeting their restoration. Understanding the underlying etiological factors leading to MuSC depletion is instrumental in identifying novel approaches to restore muscle repair and function. Our recent studies were the first to uncovered that dysregulation of mitochondrial dynamics and function, as observed in muscle wasting, impairs stem cell longevity and regenerative capacity. The overarching goal of this proposal is to restore MuSC number and function and promote muscle repair in aging and muscle wasting diseases. The combination of our proposed animal and human studies of muscle stem cells will provide novel therapeutic options using pharmaceutical and supplementation strategies. Importantly, this could have immediate translational potential to a clinical environment to improve muscle function and quality of life in patients.
1 September 2020
28 February 2022
2020
Yun Li (P)
Hospital for Sick Children
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Li, Yun
Chercheur principal
Yun Li
150 000
Engineering an organoid model of the hippocampal neurogenic niche for basic and translational research
The hippocampus is a unique structure in the human brain that contains a long-lasting neurogenic niche. During fetal development, neurons are generated by radial glia (RG), the bona fide neural stem cells of the brain. While RG in most other regions of the human brain are depleted prior to birth, some RG in the fetal hippocampus remain undifferentiated and persist for decades after birth. As a result, the hippocampus is one of the only regions of the brain where new neurons are born throughout life. However, our knowledge of the fetal hippocampal neurogenic niche is extremely limited, because of the inaccessible nature of the human fetal brain. It has been hypothesized that the long-lasting nature of the hippocampal RG critically depends on their ability to enter quiescence. Disruption of this process during fetal development likely has profound consequences on the capacity of postnatal and adult hippocampal neurogenesis. Addressing these important unknowns requires experimental models of the developing human brain, and genetic tools to manipulate the human genome, prerequisites unattainable until recently.
In the current proposal, we seek to engineer a novel organoid model of the human hippocampal neurogenic niche, to study normal and pathological development. Combining breakthrough technologies in human pluripotent stem cells (hPSCs), genome editing, and 3D organoids, my lab has recently reported that human brain development and diseases could be modeled in vitro. In unpublished results, we have created a suite of genetically engineered hPSCs to label, manipulate, and ablate hippocampal RG. These expertise and genetic tools put us at a uniquely advantageous position to carry out the proposed research. Our work will establish a significant long-term resource for studying human hippocampal neurogenesis in health and disease.
1 September 2020
28 February 2022
2020
Stephanie Protze (P)
University Health Network
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Protze
Chercheur principal
Stephanie Protze, Zachary Laksman
127 400
Developing stem cell-based biological pacemakers for patients with sick sinus syndrome
Cardiaque; maladie du sinus, dysfonctionnement du nœud sinusal, maladie de l’oreillette
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Zachary Laksman (C)
University of British Columbia
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Protze
Cochercheur
Stephanie Protze, Zachary Laksman
22 600
Developing stem cell-based biological pacemakers for patients with sick sinus syndrome
Cardiaque
Rare disease status
CPVT is a severe heart disorder that affects 1 in 10,000 people. It causes abnormal rapid beating of the heart, which can cause sudden unexpected death, often without warning signs. CPVT is called “the perfect electrical assassin” because many will go into sudden cardiac arrest without being aware that they were at risk and nearly half of affected people will die before 35 years of age.
Our established team of scientists and cardiologists is recognized for our work on CPVT. In this project, we will use stem cell technology to convert patient blood samples into heart cells (hiPSC-CMs) that carry each patient’s genetic characteristics. We will use these engineered hiPSC-CMs to identify individual genetic causes of CPVT and to develop specific treatments for each patient. Ultimately, we want to create a way to test each patient’s risk so that we can prevent unexpected early death from CPVT.
1 September 2020
28 February 2022
2020
Jo Stratton (P)
Université McGill
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Stratton
Chercheur principal
Jo Stratton
150 000
Human iPSC ependymal cells: An innovative model to study human brain in health and disease
The major technological breakthrough of the description of “Yamanaka factors” enables the reprogramming of human cells into pluripotent stem cells appropriate for deriving a diversity of human cells that have previously been inaccessible for study. This includes the study of brain cells, such as neurons and several glia cell types, that are notoriously difficult to access. The ependymal cell – the brain’s epithelial barrier cell, lines the entire ventricular system and is critically understudied largely due to a lack of reliable cellular models for their study. Ependymal cells regulate cerebrospinal fluid (CSF) circulation; and over the last decade, their role in the maintenance of CSF homeostasis is becoming much more appreciated. There is an overwhelming number of neurological conditions and diseases that are subject to ependymal cell abnormalities, which can subsequently interfere with developmental processes, regenerative mechanisms and contribute to disease progression.
Developing a robust method for generating ependymal cell cultures would not only greatly benefit my research program but would also have a wider impact on the research community, given no such method currently exists. Our objective is to use human iPSCs to develop a robust method for the routine culturing of human ependymal cells. In the process of developing this translational method, we will gain a greater understanding of the developmental timelines of human ependymal cells and apply this knowledge to better inform their regenerative potential and how they may become compromised in disease. We can use this system to understand how genes and environment interact in diseases impacting ependymal cells or impacted by ependymal cells - an accomplishment in both the fields of stem cell biology and ependymal cell biology. Ultimately, we will generate methodology that will be disseminated openly via Open-Access journals and at conferences. Along with our team of iPSC and glia experts, Drs Thomas Durcan and Luke Healy, as well as ependymal cell biologist, Jo Anne Stratton, we are well positioned to execute this project. Finally, the McGill Regenerative Network is an instrumental partner for this project, where they will support trainee stipend costs and provide network resources.
1 September 2020
28 February 2022
2020
Amy Wong (P)
Hospital for Sick Children
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Wong
Chercheur principal
Amy Wong
150 000
Elucidating the role of CFTR in human fetal lung lineage development
Poumon, poumons
Rare disease status
Cystic Fibrosis (CF) is a common genetic disease which causes difficulties in breathing, recurrent lung infections. Children under the age of 12 are not eligible for current treatments (at a cost of $300,000 CAD/year for a lifetime) aimed at targeting the main CF genetic mutation. This has been a large debate over the past few years with clinicians arguing for the early treatment of CF in children to mitigate the extent of lung damage caused by this progressively fatal disease. However, there has not been useful models to really understand the impact of CFTR functional correction in human fetuses, neonates, or young children, let alone understand the role of CFTR in normal lung development.
In 2012, I developed the first human lung in the petri dish derived solely from pluripotent stem cells. These stem cells when generated from individuals with CF enabled the use of an unlimited source of lung cells to better understand individual CF disease and personalized screens for therapeutic drugs. My lab has since expanded our stem cell-derived lung model repertoire to include fetal, immature and mature lungs derived from induced pluripotent stem cells. We have the unique models to understand how a defect in CFTR expression can impact normal development and long-term lung functions that impact therapy outcomes. We will do so my combining single cell technologies, mathematical modeling, stem cell and primary tissue models to address: 1) the origins and lineage relationship of cells expressing CFTR during development, 2) CFTR expression and function in normal lung development and, 3) the effects of CFTR mutation in lung lineage development. Our overarching goal is to understand the role of CFTR in early lung development and CF pathogenesis. Early treatment of CF lung disease will translate to meaningful therapeutic outcome that improves the health, economic and social welfare of the patient and benefits our Canadian healthcare system.
1 September 2020
28 February 2022
2020
Natasha Chang (P)
Université McGill
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Chang
Chercheur principal
Natasha Chang
150 000
Targeting muscle stem cells to enhance endogenous repair in Duchenne muscular dystrophy
Muscle, muscles; dystrophie musculaire de Duchenne, DMD
Rare disease status
Defects in the regenerative function of muscle stem cells (MuSCs) have been shown to contribute to the pathogenesis of muscular dystrophy, a group of rare and uncurable diseases that often affects young children. Using a preclinical model of merosin-deficient congenital muscular dystrophy type 1A (MDC1A) that is characterized by severe regenerative failure, we investigated the effectivity of a novel class of compounds derived from a circulating hormone that can stimulate MuSC function. We observed that these molecules significantly ameliorate disease progression. Systemic delivery of our compounds boosts MuSC numbers, promotes repair of the diseased muscle, and restores force generation in the absence of adverse cardio-vascular effects. Notably, the treatment increases life-expectancy, makes the diseased muscles stronger, and significantly improves motor function.
In our proposal we aim to further develop this discovery towards the clinics. Across three Canadian provinces, we bring together internationally renowned experts from the fields of regenerative medicine, medicinal chemistry, bioengineering, cardiovascular research, and law and ethics. The proposed research is highly translational and would establish a first-in-its-class "endogenous repair therapeutic" for muscle disease. Our work will (I) lead to the identification of compounds with improved efficacy, will (II) test the off-label use of an approved drug that stimulates the same molecular target, and will (III) lay the foundation for progression towards clinical trials.
Importantly, endogenous repair therapeutics are effective independent of underlying genetic mutations Thus, we expect our novel therapeutic approach to have broad impact on several different types of muscular dystrophy. A stem cell targeted therapeutic agent boosting skeletal muscle repair represents an unprecedented and highly disruptive discovery that pioneers a novel class of therapeutics with the potential to have a dramatic impact in the field of regenerative medicine. Our partners for this project are the Institute of Biomaterials and Biomedical Engineering (IBBME) of the University of Toronto, and the Centre de recherche du CHU Sherbrooke (CRC), the Faculté de médecine et des sciences de la santé (FMSS) and the Institut de pharmacologie de Sherbrooke (IPS) of the Université de Sherbrooke.
1 September 2020
28 February 2022
2020
Kathleen Hodgkinson (C)
Memorial University of Newfoundland
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Esseltine
Cochercheur
Jessica Esseltine, Kathleen Hodgkinson
20 000
A personalized, translational approach to understanding inherited Arrhythmogenic Right Ventricular Cardiomyopathy in Newfoundland
Cardiaque
Rare disease status
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that can cause sudden death as its first symptom. It tragically shortens the lives of healthy young people, with men affected worse than women. 50% of ARVC men will die by age 40, and 80% by 50 (5% and 20% of women).
Genes are messages written in a DNA alphabet that build proteins. Proteins are the building blocks of the cells from which we are all made. A mistake in a gene can disrupt the protein causing serious disease. ARVC in Newfoundland is caused by a DNA spelling mistake in a gene called TMEM43. This mutation was discovered in Newfoundland. Men and women both inherit the TMEM43 gene mutation, and pass it on to 50% of their children. Thus, ARVC is known as “The Newfoundland curse”.
Although all people with the TMEM43 gene mutation will get ARVC, it is not the same severity in everyone. We know nothing about what this gene change does to heart cells. We do not know why women are protected compared to men. We do not know why some dies suddenly or need a heart transplant, while others live relatively normal lives.
We have a dedicated group of families invested in helping with our research. We will collect skin samples from affected and unaffected family members and ‘reprogram’ their skin cells into induced pluripotent stem cells (iPSC). These iPSCs can become any cell type. So we can take skin cells and turn them into beating heart cells. We can then investigate how ARVC heart cells are different than their unaffected siblings. We can “repair” the DNA in these cells using CRISPR-Cas9 technology. The large families mean we can access subjects with severe forms of ARVC, and less severe forms, and access their gene negative brothers and sisters as controls.
Although concentrated within NL, ARVC caused by this mutation is seen worldwide. This research proposal will allow us to understand basic ARVC biology, which may lead to new therapies based on understanding the causes of the variation in disease presentation we see, leading to true precision medicine.
1 September 2020
28 February 2022
2020
Jessica Esseltine (P)
Memorial University of Newfoundland
Programme de soutien à la recherche innovante pour les chercheurs en début de carrière
Esseltine
Chercheur principal
Jessica Esseltine, Kathleen Hodgkinson
130 000
A personalized, translational approach to understanding inherited Arrhythmogenic Right Ventricular Cardiomyopathy in Newfoundland
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that can cause sudden death as its first symptom. It tragically shortens the lives of healthy young people, with men affected worse than women. 50% of ARVC men will die by age 40, and 80% by 50 (5% and 20% of women).
Genes are messages written in a DNA alphabet that build proteins. Proteins are the building blocks of the cells from which we are all made. A mistake in a gene can disrupt the protein causing serious disease. ARVC in Newfoundland is caused by a DNA spelling mistake in a gene called TMEM43. This mutation was discovered in Newfoundland. Men and women both inherit the TMEM43 gene mutation, and pass it on to 50% of their children. Thus, ARVC is known as “The Newfoundland curse”.
Although all people with the TMEM43 gene mutation will get ARVC, it is not the same severity in everyone. We know nothing about what this gene change does to heart cells. We do not know why women are protected compared to men. We do not know why some dies suddenly or need a heart transplant, while others live relatively normal lives.
We have a dedicated group of families invested in helping with our research. We will collect skin samples from affected and unaffected family members and ‘reprogram’ their skin cells into induced pluripotent stem cells (iPSC). These iPSCs can become any cell type. So we can take skin cells and turn them into beating heart cells. We can then investigate how ARVC heart cells are different than their unaffected siblings. We can “repair” the DNA in these cells using CRISPR-Cas9 technology. The large families mean we can access subjects with severe forms of ARVC, and less severe forms, and access their gene negative brothers and sisters as controls.
Although concentrated within NL, ARVC caused by this mutation is seen worldwide. This research proposal will allow us to understand basic ARVC biology, which may lead to new therapies based on understanding the causes of the variation in disease presentation we see, leading to true precision medicine.
1 September 2020
28 February 2022
2020
Jean-François Bouchard (C)
Université de Montréal
Subventions de soutien aux partenariats biotechnologiques
Bernier
Cochercheur
Gilbert Bernier, May Griffith, Jean-François Bouchard
66 000
Photoreceptor transplantation for the treatment of retinal degenerative diseases
Oculaire
Retinal degenerative diseases including age-related macular degeneration is the leading cause of Canadian and global vision loss after cataracts; and there are no reliable treatments. Our project aimed at photoreceptor stem cell transplantation therapy is unique Canadian and is developed by our internationally renowned interdisciplinary team with expertise in stem cell and biomaterials engineering, vision function analysis and retinal transplantation surgery. The use of novel anti-angiogenic and pro-survival agents in photoreceptor cell transplantation therapy is of interest to academia, while the resulting intellectual property is of commercial significance. Current objectives for this grant are to implement a proof-of-principle of macular transplantation therapy in non-human primates, confirm safety of the cell transplantation therapy, and validate the use of a universal donor induced pluripotent cell line for generation of therapeutic cone photoreceptors. Deliverables include the demonstration of functional vision restoration in a non-human primate model of macular degeneration, and confirmation of the functionality and non-immunogenic nature of our universal donor cell line. We anticipate that successful completion of this proposed project will help restoring or improving central vision in patients suffering from late-stage RP, Stargardt’s disease, cone dystrophies, cone/rod dystrophies and age-related macular degeneration. The clinical, social and economic impacts of this treatment is thus possibly considerable for Canadians and patients abroad. The ownership of the technology by a Canadian entity is also economically beneficial for Canadians and Canada in general. Importantly, the treatment should be widely accessible following the use of a universal donor cell line, allowing treatment of all patients at a predicted low cost. Our team also includes essential non-academic partners providing financial resources and specialized tools for retinal surgery, macular transplantation, and stem cell engineering. The involvement of non-academic partners and end-users (retinal surgeons) in this project will help us reach the commercialization phase, which is the bottleneck of translational research. This project is thus highly competitive at the international level.
1 January 2020
31 January 2022
2020
May Griffith (C)
Université de Montréal
Subventions de soutien aux partenariats biotechnologiques
Bernier
Cochercheur
Gilbert Bernier, May Griffith, Jean-François Bouchard
66 000
Photoreceptor transplantation for the treatment of retinal degenerative diseases
Oculaire
Retinal degenerative diseases including age-related macular degeneration is the leading cause of Canadian and global vision loss after cataracts; and there are no reliable treatments. Our project aimed at photoreceptor stem cell transplantation therapy is unique Canadian and is developed by our internationally renowned interdisciplinary team with expertise in stem cell and biomaterials engineering, vision function analysis and retinal transplantation surgery. The use of novel anti-angiogenic and pro-survival agents in photoreceptor cell transplantation therapy is of interest to academia, while the resulting intellectual property is of commercial significance. Current objectives for this grant are to implement a proof-of-principle of macular transplantation therapy in non-human primates, confirm safety of the cell transplantation therapy, and validate the use of a universal donor induced pluripotent cell line for generation of therapeutic cone photoreceptors. Deliverables include the demonstration of functional vision restoration in a non-human primate model of macular degeneration, and confirmation of the functionality and non-immunogenic nature of our universal donor cell line. We anticipate that successful completion of this proposed project will help restoring or improving central vision in patients suffering from late-stage RP, Stargardt’s disease, cone dystrophies, cone/rod dystrophies and age-related macular degeneration. The clinical, social and economic impacts of this treatment is thus possibly considerable for Canadians and patients abroad. The ownership of the technology by a Canadian entity is also economically beneficial for Canadians and Canada in general. Importantly, the treatment should be widely accessible following the use of a universal donor cell line, allowing treatment of all patients at a predicted low cost. Our team also includes essential non-academic partners providing financial resources and specialized tools for retinal surgery, macular transplantation, and stem cell engineering. The involvement of non-academic partners and end-users (retinal surgeons) in this project will help us reach the commercialization phase, which is the bottleneck of translational research. This project is thus highly competitive at the international level.
1 January 2020
31 January 2022
2020
Gilbert Bernier (P)
Hôpital Maisonneuve-Rosemont
Subventions de soutien aux partenariats biotechnologiques
Bernier
Chercheur principal
Gilbert Bernier, May Griffith, Jean-François Bouchard
368 000
Photoreceptor transplantation for the treatment of retinal degenerative diseases
Oculaire; diverses maladies
Retinal degenerative diseases including age-related macular degeneration is the leading cause of Canadian and global vision loss after cataracts; and there are no reliable treatments. Our project aimed at photoreceptor stem cell transplantation therapy is unique Canadian and is developed by our internationally renowned interdisciplinary team with expertise in stem cell and biomaterials engineering, vision function analysis and retinal transplantation surgery. The use of novel anti-angiogenic and pro-survival agents in photoreceptor cell transplantation therapy is of interest to academia, while the resulting intellectual property is of commercial significance. Current objectives for this grant are to implement a proof-of-principle of macular transplantation therapy in non-human primates, confirm safety of the cell transplantation therapy, and validate the use of a universal donor induced pluripotent cell line for generation of therapeutic cone photoreceptors. Deliverables include the demonstration of functional vision restoration in a non-human primate model of macular degeneration, and confirmation of the functionality and non-immunogenic nature of our universal donor cell line. We anticipate that successful completion of this proposed project will help restoring or improving central vision in patients suffering from late-stage RP, Stargardt’s disease, cone dystrophies, cone/rod dystrophies and age-related macular degeneration. The clinical, social and economic impacts of this treatment is thus possibly considerable for Canadians and patients abroad. The ownership of the technology by a Canadian entity is also economically beneficial for Canadians and Canada in general. Importantly, the treatment should be widely accessible following the use of a universal donor cell line, allowing treatment of all patients at a predicted low cost. Our team also includes essential non-academic partners providing financial resources and specialized tools for retinal surgery, macular transplantation, and stem cell engineering. The involvement of non-academic partners and end-users (retinal surgeons) in this project will help us reach the commercialization phase, which is the bottleneck of translational research. This project is thus highly competitive at the international level.
1 January 2020
31 January 2022
2020
Massimiliano Paganelli (P)
CHU Sainte-Justine
Subventions de soutien aux partenariats biotechnologiques
Paganelli
Chercheur principal
Massimiliano Paganelli
500 000
iPSC-derived encapsulated liver tissue to treat acute liver failure: pivotal confirmation in large animals
Insuffisance hépatique
Liver failure is the common outcome of most progressive liver diseases, affecting millions of people worldwide. Acute liver failure (ALF) is an extremely severe, progressive syndrome resulting from a sudden insult (like a drug, virus or toxin) to a previously healthy liver that affects thousands of people every year. Patients with ALF need to receive a liver transplant within days from the diagnosis, before their disease becomes irreversibly too severe. Over the last 3 years, with the support of the Stem Cell Network and other provincial and federal funding agencies, we developed an implantable product derived from human stem cells capable of treating ALF, avoiding transplantation. We already showed that what we call the Encapsulated Liver Tissue (ELT) is capable to perform mature liver function in a dish. We also showed that the ELT is safe and effective in treating ALF in rodents, without the risk of rejection or tumor formation. The ELT showed a significant competitive edge over similar products that are being developed worldwide. To promote the development and maturation of this technology and ease its translation to the patients, we created a spin-off company (Morphocell Technologies) and licensed our IP. We are already working with this Canadian regenerative medicine company and with the Centre for Commercialization of Regenerative Medicine (CCRM) to transform the ELT into a safe product for human use. With this project, we will collaborate with Morphocell, CCRM and other Canadian leading experts and stakeholders to confirm the safety and efficacy of the ELT in a large animal model of ALF. This will allow moving this promising treatment towards a first clinical trial in patients with ALF. This grant will support Canadian leadership in this field, help the growth of a promising Canadian biotechnology company (contributing to job creation) and foster the creation of unique scientific and technical expertise. If successful, this project will bring closer to the patients what has been widely recognized as a disruptive treatment for liver disease, which could save and improve the quality of life of thousands of patients with ALF and hundreds of thousands with chronic liver failure, worldwide.
1 January 2020
31 January 2022
2020
Corrine Hoesli (C)
Université McGill
Subventions de soutien aux partenariats biotechnologiques
Kieffer
Cochercheur
Tim Kieffer, James Piret, Steven Paraskevas, Megan Levings, Corrine Hoesli
130 000
A Bioprinted Insulin-Producing Device for Diabetes
Diabète
Injecting insulin has been extensively used to treat diabetes for almost a century. However, daily insulin injections do not adequately maintain blood sugar at normal levels, leading to damage throughout the body. While excellent blood sugar control without insulin injection can be achieved by transplantation of donor pancreas or insulin-producing islets, this strategy is severely limited by lack of available donors and requirement for life-long immune-suppression, thus hampering its broader application to treat diabetes. Aspect Biosystems has developed a proprietary bioprinting platform for manufacturing human tissues on demand to replace the need for donor organ transplants. This proposal aims to accelerate Aspect’s pre-clinical development of a therapeutic pancreatic tissue patch as a therapy for type 1 diabetes that does not rely on daily insulin injections or cadaveric donor islets. This objective will be accomplished by bringing together Canadian expertise in islet transplant biology led by academic PI, Dr. Timothy Kieffer and an existing collaborative network. The team will work together to tackle three key challenge areas for islet transplantation programs by: 1) providing a sustainable stem cell-derived source of insulin-producing beta cells that can be manufactured to scale for therapeutic efficacy and has already been shown to restore euglycemia in gold-standard animal models of diabetes in Dr. Kieffer’s lab; 2) offering device manufacturing and material processing solutions for optimization of pancreatic tissue patch design that maximally supports beta-cell fitness and function in a manner that maintains immune-protection through bioengineering capabilities and analytical tools in the laboratories of Drs. Corinne Hoesli and James Piret; and 3) access to surgical transplantation expertise in order to confidently demonstrate pre-clinical efficacy of an immune-protected pancreatic tissue patch using human relevant immune cell tools developed by Dr. Megan Levings in addition to human islet transplantation clinical insight from Dr. Steven Paraskevas as an anticipated therapeutic tissue patch device adopter. The project will provide direct benefits to Canada through improved health for patients with diabetes and reduced burden of health care cost, while also creating commercial opportunities and a future revenue stream for a Canadian based biotechnology company aiming to enter the regenerative medicine market.
1 January 2020
31 January 2022
2020
Megan Levings (C)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Kieffer
Cochercheur
Tim Kieffer, James Piret, Steven Paraskevas, Megan Levings, Corrine Hoesli
90 000
A Bioprinted Insulin-Producing Device for Diabetes
Diabète
Injecting insulin has been extensively used to treat diabetes for almost a century. However, daily insulin injections do not adequately maintain blood sugar at normal levels, leading to damage throughout the body. While excellent blood sugar control without insulin injection can be achieved by transplantation of donor pancreas or insulin-producing islets, this strategy is severely limited by lack of available donors and requirement for life-long immune-suppression, thus hampering its broader application to treat diabetes. Aspect Biosystems has developed a proprietary bioprinting platform for manufacturing human tissues on demand to replace the need for donor organ transplants. This proposal aims to accelerate Aspect’s pre-clinical development of a therapeutic pancreatic tissue patch as a therapy for type 1 diabetes that does not rely on daily insulin injections or cadaveric donor islets. This objective will be accomplished by bringing together Canadian expertise in islet transplant biology led by academic PI, Dr. Timothy Kieffer and an existing collaborative network. The team will work together to tackle three key challenge areas for islet transplantation programs by: 1) providing a sustainable stem cell-derived source of insulin-producing beta cells that can be manufactured to scale for therapeutic efficacy and has already been shown to restore euglycemia in gold-standard animal models of diabetes in Dr. Kieffer’s lab; 2) offering device manufacturing and material processing solutions for optimization of pancreatic tissue patch design that maximally supports beta-cell fitness and function in a manner that maintains immune-protection through bioengineering capabilities and analytical tools in the laboratories of Drs. Corinne Hoesli and James Piret; and 3) access to surgical transplantation expertise in order to confidently demonstrate pre-clinical efficacy of an immune-protected pancreatic tissue patch using human relevant immune cell tools developed by Dr. Megan Levings in addition to human islet transplantation clinical insight from Dr. Steven Paraskevas as an anticipated therapeutic tissue patch device adopter. The project will provide direct benefits to Canada through improved health for patients with diabetes and reduced burden of health care cost, while also creating commercial opportunities and a future revenue stream for a Canadian based biotechnology company aiming to enter the regenerative medicine market.
1 January 2020
31 January 2022
2020
Steven Paraskevas (C)
Université McGill
Subventions de soutien aux partenariats biotechnologiques
Kieffer
Cochercheur
Tim Kieffer, James Piret, Steven Paraskevas, Megan Levings, Corrine Hoesli
70 000
A Bioprinted Insulin-Producing Device for Diabetes
Diabète
Injecting insulin has been extensively used to treat diabetes for almost a century. However, daily insulin injections do not adequately maintain blood sugar at normal levels, leading to damage throughout the body. While excellent blood sugar control without insulin injection can be achieved by transplantation of donor pancreas or insulin-producing islets, this strategy is severely limited by lack of available donors and requirement for life-long immune-suppression, thus hampering its broader application to treat diabetes. Aspect Biosystems has developed a proprietary bioprinting platform for manufacturing human tissues on demand to replace the need for donor organ transplants. This proposal aims to accelerate Aspect’s pre-clinical development of a therapeutic pancreatic tissue patch as a therapy for type 1 diabetes that does not rely on daily insulin injections or cadaveric donor islets. This objective will be accomplished by bringing together Canadian expertise in islet transplant biology led by academic PI, Dr. Timothy Kieffer and an existing collaborative network. The team will work together to tackle three key challenge areas for islet transplantation programs by: 1) providing a sustainable stem cell-derived source of insulin-producing beta cells that can be manufactured to scale for therapeutic efficacy and has already been shown to restore euglycemia in gold-standard animal models of diabetes in Dr. Kieffer’s lab; 2) offering device manufacturing and material processing solutions for optimization of pancreatic tissue patch design that maximally supports beta-cell fitness and function in a manner that maintains immune-protection through bioengineering capabilities and analytical tools in the laboratories of Drs. Corinne Hoesli and James Piret; and 3) access to surgical transplantation expertise in order to confidently demonstrate pre-clinical efficacy of an immune-protected pancreatic tissue patch using human relevant immune cell tools developed by Dr. Megan Levings in addition to human islet transplantation clinical insight from Dr. Steven Paraskevas as an anticipated therapeutic tissue patch device adopter. The project will provide direct benefits to Canada through improved health for patients with diabetes and reduced burden of health care cost, while also creating commercial opportunities and a future revenue stream for a Canadian based biotechnology company aiming to enter the regenerative medicine market.
1 January 2020
31 January 2022
2020
James Piret (C)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Kieffer
Cochercheur
Tim Kieffer, James Piret, Steven Paraskevas, Megan Levings, Corrine Hoesli
80 000
A Bioprinted Insulin-Producing Device for Diabetes
Diabète
Injecting insulin has been extensively used to treat diabetes for almost a century. However, daily insulin injections do not adequately maintain blood sugar at normal levels, leading to damage throughout the body. While excellent blood sugar control without insulin injection can be achieved by transplantation of donor pancreas or insulin-producing islets, this strategy is severely limited by lack of available donors and requirement for life-long immune-suppression, thus hampering its broader application to treat diabetes. Aspect Biosystems has developed a proprietary bioprinting platform for manufacturing human tissues on demand to replace the need for donor organ transplants. This proposal aims to accelerate Aspect’s pre-clinical development of a therapeutic pancreatic tissue patch as a therapy for type 1 diabetes that does not rely on daily insulin injections or cadaveric donor islets. This objective will be accomplished by bringing together Canadian expertise in islet transplant biology led by academic PI, Dr. Timothy Kieffer and an existing collaborative network. The team will work together to tackle three key challenge areas for islet transplantation programs by: 1) providing a sustainable stem cell-derived source of insulin-producing beta cells that can be manufactured to scale for therapeutic efficacy and has already been shown to restore euglycemia in gold-standard animal models of diabetes in Dr. Kieffer’s lab; 2) offering device manufacturing and material processing solutions for optimization of pancreatic tissue patch design that maximally supports beta-cell fitness and function in a manner that maintains immune-protection through bioengineering capabilities and analytical tools in the laboratories of Drs. Corinne Hoesli and James Piret; and 3) access to surgical transplantation expertise in order to confidently demonstrate pre-clinical efficacy of an immune-protected pancreatic tissue patch using human relevant immune cell tools developed by Dr. Megan Levings in addition to human islet transplantation clinical insight from Dr. Steven Paraskevas as an anticipated therapeutic tissue patch device adopter. The project will provide direct benefits to Canada through improved health for patients with diabetes and reduced burden of health care cost, while also creating commercial opportunities and a future revenue stream for a Canadian based biotechnology company aiming to enter the regenerative medicine market.
1 January 2020
31 January 2022
2020
Tim Kieffer (P)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Kieffer
Chercheur principal
Tim Kieffer, James Piret, Steven Paraskevas, Megan Levings, Corrine Hoesli
130 000
A Bioprinted Insulin-Producing Device for Diabetes
Diabète
Injecting insulin has been extensively used to treat diabetes for almost a century. However, daily insulin injections do not adequately maintain blood sugar at normal levels, leading to damage throughout the body. While excellent blood sugar control without insulin injection can be achieved by transplantation of donor pancreas or insulin-producing islets, this strategy is severely limited by lack of available donors and requirement for life-long immune-suppression, thus hampering its broader application to treat diabetes. Aspect Biosystems has developed a proprietary bioprinting platform for manufacturing human tissues on demand to replace the need for donor organ transplants. This proposal aims to accelerate Aspect’s pre-clinical development of a therapeutic pancreatic tissue patch as a therapy for type 1 diabetes that does not rely on daily insulin injections or cadaveric donor islets. This objective will be accomplished by bringing together Canadian expertise in islet transplant biology led by academic PI, Dr. Timothy Kieffer and an existing collaborative network. The team will work together to tackle three key challenge areas for islet transplantation programs by: 1) providing a sustainable stem cell-derived source of insulin-producing beta cells that can be manufactured to scale for therapeutic efficacy and has already been shown to restore euglycemia in gold-standard animal models of diabetes in Dr. Kieffer’s lab; 2) offering device manufacturing and material processing solutions for optimization of pancreatic tissue patch design that maximally supports beta-cell fitness and function in a manner that maintains immune-protection through bioengineering capabilities and analytical tools in the laboratories of Drs. Corinne Hoesli and James Piret; and 3) access to surgical transplantation expertise in order to confidently demonstrate pre-clinical efficacy of an immune-protected pancreatic tissue patch using human relevant immune cell tools developed by Dr. Megan Levings in addition to human islet transplantation clinical insight from Dr. Steven Paraskevas as an anticipated therapeutic tissue patch device adopter. The project will provide direct benefits to Canada through improved health for patients with diabetes and reduced burden of health care cost, while also creating commercial opportunities and a future revenue stream for a Canadian based biotechnology company aiming to enter the regenerative medicine market.
1 January 2020
31 January 2022
2020
Dean Fergusson (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien aux partenariats biotechnologiques
Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation, which is not always feasible. Novel therapies for surfactant deficiencies are urgently needed.
We have engineered a novel regenerative medicine platform based on a gene therapy to cure these untreatable lung diseases. SP-B deficiency is Inspire Biotherapeutics’ lead indication. Our platform utilizes an engineered AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls.
Here, we propose to overcome the main obstacles to bringing a regenerative gene therapy into patients: establish the efficient large-scale manufacturing of AAV and demonstrate vector safety and tolerability in toxicology studies. The scalable AAV manufacturing process will enable the expansion of our AAVenger platform, utilizing our patented gene therapy technology and novel molecular and genetic tools, to produce clinical trial-ready gene therapies for a wide range of life-threatening and debilitating lung diseases affecting Canadians and patients world-wide. Our multi-disciplinary team has successfully collaborated over the past three years and highlights Canadian excellence and leadership in regenerative medicine, gene therapy, manufacturing and clinical trials. This grant will support the acceleration of a promising Canadian Regenerative Medicine biotechnology company, grow unique scientific and technical expertise, and create jobs for a new breed of HQP.
1 September 2020
28 February 2022
2020
Sarah Wooton (C)
University of Guelph
Subventions de soutien aux partenariats biotechnologiques
Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation, which is not always feasible. Novel therapies for surfactant deficiencies are urgently needed.
We have engineered a novel regenerative medicine platform based on a gene therapy to cure these untreatable lung diseases. SP-B deficiency is Inspire Biotherapeutics’ lead indication. Our platform utilizes an engineered AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls.
Here, we propose to overcome the main obstacles to bringing a regenerative gene therapy into patients: establish the efficient large-scale manufacturing of AAV and demonstrate vector safety and tolerability in toxicology studies. The scalable AAV manufacturing process will enable the expansion of our AAVenger platform, utilizing our patented gene therapy technology and novel molecular and genetic tools, to produce clinical trial-ready gene therapies for a wide range of life-threatening and debilitating lung diseases affecting Canadians and patients world-wide. Our multi-disciplinary team has successfully collaborated over the past three years and highlights Canadian excellence and leadership in regenerative medicine, gene therapy, manufacturing and clinical trials. This grant will support the acceleration of a promising Canadian Regenerative Medicine biotechnology company, grow unique scientific and technical expertise, and create jobs for a new breed of HQP.
1 September 2020
28 February 2022
2020
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien aux partenariats biotechnologiques
Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation, which is not always feasible. Novel therapies for surfactant deficiencies are urgently needed.
We have engineered a novel regenerative medicine platform based on a gene therapy to cure these untreatable lung diseases. SP-B deficiency is Inspire Biotherapeutics’ lead indication. Our platform utilizes an engineered AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls.
Here, we propose to overcome the main obstacles to bringing a regenerative gene therapy into patients: establish the efficient large-scale manufacturing of AAV and demonstrate vector safety and tolerability in toxicology studies. The scalable AAV manufacturing process will enable the expansion of our AAVenger platform, utilizing our patented gene therapy technology and novel molecular and genetic tools, to produce clinical trial-ready gene therapies for a wide range of life-threatening and debilitating lung diseases affecting Canadians and patients world-wide. Our multi-disciplinary team has successfully collaborated over the past three years and highlights Canadian excellence and leadership in regenerative medicine, gene therapy, manufacturing and clinical trials. This grant will support the acceleration of a promising Canadian Regenerative Medicine biotechnology company, grow unique scientific and technical expertise, and create jobs for a new breed of HQP.
1 September 2020
28 February 2022
2020
Peter Zandstra (P)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Zandstra
Chercheur principal
Peter Zandstra, David Knapp, Robert Holt
266 300
Enabling a platform for customized pluripotent stem cell derived T-cell therapies
Sang, CAR-T
Underlying the genesis and progression of many chronic illnesses including cancer, diabetes, heart disease, auto-immunity, and immunodeficiency, is dysfunction of immune cells. T-lymphocyte cells develop within the thymus, and are part of the adaptive immune system which includes cytotoxic T-cells that mediate defence against cancer cells and intracellular pathogens, including viruses. Cellular therapies with genetically engineered cytotoxic T-cells, e.g. CAR or TCR T-cells, designed to attack cancer cells, have shown tremendous efficacy as anti-cancer therapies. However, as mature T-cells from patients are used in this process, successful implementation of this strategy is limited by high treatment costs, low cell yields, and compromised function of the thymus in some patients. Consequently, a robust and renewable supply of normal and engineered T-cells would transform clinical applications.
Our research team is led by Dr. Peter Zandstra, a world leader and innovator in stem cell-based, Dr. Robert Holt, an expert in T-cell receptor engineering and leading lead in a pan-Canadian effort to conduct the first Phase I/II anti-CD19 CAR T-cell therapy trial in Canada using Canadian-made vectors and cells, and Dr. David Knapp, an emerging leader with expertise in applying cutting-edge genomic approaches to advance the study of blood cell differentiation. Dr. Zandstra and collaborator Dr. Juan Carlos Zúñiga-Pflücker previously established a clinically relevant in vitro engineered thymic niche system to generate progenitor T-cells from human blood stem cells. The combination of this technology with genetically modified human pluripotent stem cells (hPSC) could profoundly transform therapeutic applications of immune system related diseases.
To make T-cell therapies, including CAR T-cells, more scalable, cost-effective, and rapidly available to Canadians, our research team will work with Notch Therapeutics Inc., founded by Drs. Zandstra and Zúñiga-Pflücker, on developing a platform, called the Engineered Thymic Niche (ETN), to differentiate T-cells from human pluripotent stem cells (hPSCs), an unlimited cell source. We will use this platform to develop proof of concept T-cell therapeutics including engineered cytotoxic T-cells targeting Epstein Barr Virus (EBV) infected cells, that will lay the foundation for clinical trials to treat cancer and other diseases, and will enable multiple cell therapeutic applications.
1 September 2020
28 February 2022
2020
David Knapp (C)
Université de Montréal
Subventions de soutien aux partenariats biotechnologiques
Zandstra
Cochercheur
Peter Zandstra, David Knapp, Robert Holt
40 000
Enabling a platform for customized pluripotent stem cell derived T-cell therapies
Sang, CAR-T
Underlying the genesis and progression of many chronic illnesses including cancer, diabetes, heart disease, auto-immunity, and immunodeficiency, is dysfunction of immune cells. T-lymphocyte cells develop within the thymus, and are part of the adaptive immune system which includes cytotoxic T-cells that mediate defence against cancer cells and intracellular pathogens, including viruses. Cellular therapies with genetically engineered cytotoxic T-cells, e.g. CAR or TCR T-cells, designed to attack cancer cells, have shown tremendous efficacy as anti-cancer therapies. However, as mature T-cells from patients are used in this process, successful implementation of this strategy is limited by high treatment costs, low cell yields, and compromised function of the thymus in some patients. Consequently, a robust and renewable supply of normal and engineered T-cells would transform clinical applications.
Our research team is led by Dr. Peter Zandstra, a world leader and innovator in stem cell-based, Dr. Robert Holt, an expert in T-cell receptor engineering and leading lead in a pan-Canadian effort to conduct the first Phase I/II anti-CD19 CAR T-cell therapy trial in Canada using Canadian-made vectors and cells, and Dr. David Knapp, an emerging leader with expertise in applying cutting-edge genomic approaches to advance the study of blood cell differentiation. Dr. Zandstra and collaborator Dr. Juan Carlos Zúñiga-Pflücker previously established a clinically relevant in vitro engineered thymic niche system to generate progenitor T-cells from human blood stem cells. The combination of this technology with genetically modified human pluripotent stem cells (hPSC) could profoundly transform therapeutic applications of immune system related diseases.
To make T-cell therapies, including CAR T-cells, more scalable, cost-effective, and rapidly available to Canadians, our research team will work with Notch Therapeutics Inc., founded by Drs. Zandstra and Zúñiga-Pflücker, on developing a platform, called the Engineered Thymic Niche (ETN), to differentiate T-cells from human pluripotent stem cells (hPSCs), an unlimited cell source. We will use this platform to develop proof of concept T-cell therapeutics including engineered cytotoxic T-cells targeting Epstein Barr Virus (EBV) infected cells, that will lay the foundation for clinical trials to treat cancer and other diseases, and will enable multiple cell therapeutic applications.
1 September 2020
28 February 2022
2020
Robert Holt (C)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Zandstra
Cochercheur
Peter Zandstra, David Knapp, Robert Holt
43 700
Enabling a platform for customized pluripotent stem cell derived T-cell therapies
Sang, CAR-T
Underlying the genesis and progression of many chronic illnesses including cancer, diabetes, heart disease, auto-immunity, and immunodeficiency, is dysfunction of immune cells. T-lymphocyte cells develop within the thymus, and are part of the adaptive immune system which includes cytotoxic T-cells that mediate defence against cancer cells and intracellular pathogens, including viruses. Cellular therapies with genetically engineered cytotoxic T-cells, e.g. CAR or TCR T-cells, designed to attack cancer cells, have shown tremendous efficacy as anti-cancer therapies. However, as mature T-cells from patients are used in this process, successful implementation of this strategy is limited by high treatment costs, low cell yields, and compromised function of the thymus in some patients. Consequently, a robust and renewable supply of normal and engineered T-cells would transform clinical applications.
Our research team is led by Dr. Peter Zandstra, a world leader and innovator in stem cell-based, Dr. Robert Holt, an expert in T-cell receptor engineering and leading lead in a pan-Canadian effort to conduct the first Phase I/II anti-CD19 CAR T-cell therapy trial in Canada using Canadian-made vectors and cells, and Dr. David Knapp, an emerging leader with expertise in applying cutting-edge genomic approaches to advance the study of blood cell differentiation. Dr. Zandstra and collaborator Dr. Juan Carlos Zúñiga-Pflücker previously established a clinically relevant in vitro engineered thymic niche system to generate progenitor T-cells from human blood stem cells. The combination of this technology with genetically modified human pluripotent stem cells (hPSC) could profoundly transform therapeutic applications of immune system related diseases.
To make T-cell therapies, including CAR T-cells, more scalable, cost-effective, and rapidly available to Canadians, our research team will work with Notch Therapeutics Inc., founded by Drs. Zandstra and Zúñiga-Pflücker, on developing a platform, called the Engineered Thymic Niche (ETN), to differentiate T-cells from human pluripotent stem cells (hPSCs), an unlimited cell source. We will use this platform to develop proof of concept T-cell therapeutics including engineered cytotoxic T-cells targeting Epstein Barr Virus (EBV) infected cells, that will lay the foundation for clinical trials to treat cancer and other diseases, and will enable multiple cell therapeutic applications.
1 September 2020
28 February 2022
2020
Bartha Knoppers (P)
Université McGill
Application et société
Knoppers
Chercheur principal
Bartha Knoppers
74 836
Ethical and Legal Framework for Direct-to-Participant (DTP) Recruitment
QEJS, questions éthiques, juridiques et sociales; recrutement des patients
An important impediment to research progress in stem cell research, particularly for rare diseases, is the recruitment of participants for data and sample collection. Addressing this challenge, Canadian researchers are currently exploring the use of international Direct-to-Participant (DTP) recruitment, a novel recruitment strategy harnessing the communication and networking potential of the internet and social media platforms. DTP will impact how research studies are conducted as the model allows the direct recruitment, consenting and enrollment of participants via the internet without involvement from other researchers or institutions/hospitals. Presently, the benefits of DTP recruitment are unknown while little research has been conducted regarding the ethical/legal implications of this methodology. Likewise, there is a lack of national and international guidance for the appropriate and legitimate uses of DTP recruitment, as well as how best to resolve the ethical/legal concerns that can unfold, since many countries – including Canada – have yet to clearly address the issue. The absence of proper governance presents challenges for researchers when navigating the different regulatory and ethical requirements and increases the likelihood of risks to participants.
The main objective of this project is to fill this ethical and policy gap by: i) examining the ethical/legal issues of international DTP recruitment (for adult and minor participants), and ii) yielding concrete, practical ethical guidance and tools for Canadian researchers and REBs. In collaboration with the Program for Individualized Cystic Fibrosis Therapy (CFIT) at SickKids, we will first build a case study to examine the feasibility and utility of international DTP recruitment, while producing practical, context specific governance framework and recruitment tools. Knowledge and pragmatic experience gained from the CFIT case study, along with consultations with national stakeholders (REB representatives, researchers, oversight agencies and policy makers), will contribute to the development of Canadian Best Practice Guidelines for DTP recruitment. As innovative and fundamental resources for Canadian REBs and researchers, the guidelines and practical tools will directly address an immediate need for clear policy and guidance for international DTP recruitment in stem cell research. They will also set the standards for Canada and internationally, consolidating Canada’s position as a leader in policy development.
1 January 2020
31 January 2022
2020
Kelly Cobey (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions du programme Applications et Société
Thébaud
Cochercheur
Bernard Thébaud, Manoj Lalu, Kelly Cobey
15 000
Clearing-up the stem-cell-mess: Delphi-based definition and reporting guidelines to improve transparency in MSC research
QEJS, questions éthiques, juridiques et sociales, CSM
Mesenchymal Stromal Cells (MSCs) have been tested in more than 1000 clinical trials. Despite promising results in different laboratory models, MSC clinical trials demonstrate inconsistent results regarding their clinical efficacy. One explanation is that there is a wide variation in the quality of the descriptions of what they define as an MSC, how they produced MSCs, and which patients they treated. As a consequence, the results of these studies are difficult to reproduce, compare and generalize. Therefore, it is critical that our research community develops a clear definition of what MSCs are, as well as guidelines on how to properly report MSC clinical trials.
To address these concerns, we will recruit international experts on MSCs to participate in a consensus generating process called the Delphi method. Our Delphi consists of three rounds of consensus building questions answered electronically. In the first three rounds, a Core Group, along with a broader group of MSC researchers, answer specific questions via an online survey about how to define MSCs and what items should be mandatory to properly report results of an MSC clinical study. A additional fourth round occurs in person and will be attended by the Core Group. Between Delphi rounds the questionnaire is modified according to the experts’ responses. Feedback from the group's responses (e.g. aggregate ratings of items, comments) are provided to each respondent after each round to build consensus. Inclusion or exclusion of an item will be defined by 80% agreement in responses among the group.
Providing a universally accepted definition of MSCs and guidelines on how to report clinical trials using MSCs will improve the quality, transparency and reproducibility of MSC research. To ensure uptake of our guidelines, we will develop tools and resources to increase awareness and to implement our consensus definition and reporting guidelines. This will include a dedicated website of resources that hosts freely available educational content, FAQ sheets, infographics, examples of how to successfully apply the definition and reporting guideline, and a list of stakeholders who have endorsed and implemented our recommendations.
“To maximize the benefit to society, you need not to just do research but do it well”, Doug Altman.
1 September 2020
28 February 2022
2020
Manoj Lalu (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions du programme Applications et Société
Thébaud
Cochercheur
Bernard Thébaud, Manoj Lalu, Kelly Cobey
58 500
Clearing-up the stem-cell-mess: Delphi-based definition and reporting guidelines to improve transparency in MSC research
QEJS, questions éthiques, juridiques et sociales, CSM
Mesenchymal Stromal Cells (MSCs) have been tested in more than 1000 clinical trials. Despite promising results in different laboratory models, MSC clinical trials demonstrate inconsistent results regarding their clinical efficacy. One explanation is that there is a wide variation in the quality of the descriptions of what they define as an MSC, how they produced MSCs, and which patients they treated. As a consequence, the results of these studies are difficult to reproduce, compare and generalize. Therefore, it is critical that our research community develops a clear definition of what MSCs are, as well as guidelines on how to properly report MSC clinical trials.
To address these concerns, we will recruit international experts on MSCs to participate in a consensus generating process called the Delphi method. Our Delphi consists of three rounds of consensus building questions answered electronically. In the first three rounds, a Core Group, along with a broader group of MSC researchers, answer specific questions via an online survey about how to define MSCs and what items should be mandatory to properly report results of an MSC clinical study. A additional fourth round occurs in person and will be attended by the Core Group. Between Delphi rounds the questionnaire is modified according to the experts’ responses. Feedback from the group's responses (e.g. aggregate ratings of items, comments) are provided to each respondent after each round to build consensus. Inclusion or exclusion of an item will be defined by 80% agreement in responses among the group.
Providing a universally accepted definition of MSCs and guidelines on how to report clinical trials using MSCs will improve the quality, transparency and reproducibility of MSC research. To ensure uptake of our guidelines, we will develop tools and resources to increase awareness and to implement our consensus definition and reporting guidelines. This will include a dedicated website of resources that hosts freely available educational content, FAQ sheets, infographics, examples of how to successfully apply the definition and reporting guideline, and a list of stakeholders who have endorsed and implemented our recommendations.
“To maximize the benefit to society, you need not to just do research but do it well”, Doug Altman.
1 September 2020
28 February 2022
2020
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions du programme Applications et Société
Thébaud
Chercheur principal
Bernard Thébaud, Manoj Lalu, Kelly Cobey
101 500
Clearing-up the stem-cell-mess: Delphi-based definition and reporting guidelines to improve transparency in MSC research
QEJS, questions éthiques, juridiques et sociales, CSM
Mesenchymal Stromal Cells (MSCs) have been tested in more than 1000 clinical trials. Despite promising results in different laboratory models, MSC clinical trials demonstrate inconsistent results regarding their clinical efficacy. One explanation is that there is a wide variation in the quality of the descriptions of what they define as an MSC, how they produced MSCs, and which patients they treated. As a consequence, the results of these studies are difficult to reproduce, compare and generalize. Therefore, it is critical that our research community develops a clear definition of what MSCs are, as well as guidelines on how to properly report MSC clinical trials.
To address these concerns, we will recruit international experts on MSCs to participate in a consensus generating process called the Delphi method. Our Delphi consists of three rounds of consensus building questions answered electronically. In the first three rounds, a Core Group, along with a broader group of MSC researchers, answer specific questions via an online survey about how to define MSCs and what items should be mandatory to properly report results of an MSC clinical study. A additional fourth round occurs in person and will be attended by the Core Group. Between Delphi rounds the questionnaire is modified according to the experts’ responses. Feedback from the group's responses (e.g. aggregate ratings of items, comments) are provided to each respondent after each round to build consensus. Inclusion or exclusion of an item will be defined by 80% agreement in responses among the group.
Providing a universally accepted definition of MSCs and guidelines on how to report clinical trials using MSCs will improve the quality, transparency and reproducibility of MSC research. To ensure uptake of our guidelines, we will develop tools and resources to increase awareness and to implement our consensus definition and reporting guidelines. This will include a dedicated website of resources that hosts freely available educational content, FAQ sheets, infographics, examples of how to successfully apply the definition and reporting guideline, and a list of stakeholders who have endorsed and implemented our recommendations.
“To maximize the benefit to society, you need not to just do research but do it well”, Doug Altman.
1 September 2020
28 February 2022
2022
Véronique Moulin (P)
Université Laval
Subventions de soutien des essais cliniques
Moulin
Chercheur principal
Véronique Moulin
581 700
Tissue engineering to treat Canadian burn patients: the Self-Assembled Skin Substitutes (SASS)
The standard treatment of burn wounds is based on skin autografts. When burn surface area covers more than 50% of the total body surface area, the availability of donor sites is drastically reduced and the risk of mortality and morbidity is higher. A tissue engineering method developed in our lab make it possible to produce autologous Self-Assembly Skin Substitutes (SASS) that permanently cover wounds. Health Canada has accepted an early phase clinical trial and 14 patients have already been enrolled in 7 burn units across Canada. Power analysis calculates that at least 17 patients are needed to demonstrate that graft take percentages of SASS grafts are not more than 10% lower than the graft take of skin autografts. The objective is to complete the clinical trial and apply for a Notice of Compliance with Conditions (NOC/c) from Heath Canada. Thus, we plan to treat patients (to reach at least N=17) and assess initial graft take and post-grafting scar development over 2 years. Once obtained, we will summarize the results and apply for a NOC/c, which represents an accelerated pathway for drug approval in Canada. Indeed, the SASS grafts meet NOC/c requirements because they reduce risks for patients with rare and severely debilitating condition. After completing the grant, we expect to obtain full authorization to offer our product in Canada. To carry out recruitment and treatment, we will collaborate with Canadian surgeons dedicated to the treatment of burns. We speculate that SASS treatment will have economic and social benefits. Our preliminary results demonstrate that the treatment decreases morbidity compared to standard treatments (i.e., by decreasing the need for further surgeries and decreasing pain) and improves the quality of the post-burn scars. Our interdisciplinary team is composed of four internationally renowned researchers in regenerative medicine from two universities and plastic surgeons working in major Canadian burn units. Manufacturing SASS in a tissue processing centre built and directed by our team, we are the only Canadian team dedicated to the reconstruction of organized tissues to treat burn patients. Partners include U Laval, McGill, CHU, ThéCell, MRM and UL Foundation. Upon Health Canada approval, we will be the first in Canada to routinely and successfully treat patients with autologous reconstructed skin.
1 avril 2022
31 janvier 2025
2022
David Thompson (P)
University of British Columbia
Subventions de soutien des essais cliniques
Thompson
Chercheur principal
David Thompson
1 000 000
Clinical Trial of the First Gene-Edited Cell Replacement Therapy for Type 1 Diabetes
Diabetes results from insufficient production of the glucose lowering hormone insulin from pancreatic islet cells. Severe forms of the disease used to be fatal until Canadians discovered insulin in 1921. While life-sustaining, patients with diabetes face a life of daily insulin injections and blood glucose measurements and suffer from debilitating complications. Transplant of islets obtained from organ donors is a highly effective treatmen, with some remaining insulin-independent more than ten years. However, this therapy is severely restricted by limited supply of donor organs. ViaCyte is developing a pancreatic progenitor product from stem cells that represents a renewable source of cells, and an implantable device to contain the cells. Our clinical testing of this potential product with low doses of cells indicates the procedure is safe and the device supports both the maturation and function of the implanted cells. In a patient implanted with a higher dose of cells, peak insulin use was reduced >70% and blood glucose levels were maintained in the healthy range >90% of the time. The ViaCyte stem cells have now been genetically engineered to escape detection by the immune system. As a world’s first, we will embark on clinical trials in patients with type 1 diabetes to examine if these cells can restore normal control of blood glucose levels and eliminate insulin injections, in the absence of chronic immunosuppression. Our team will apply unique and rigorous assessments of graft function including glucose-clamps, and determining responsiveness to incretin hormones. The team consists of Dr. Kieffer, an authority on cell therapy for diabetes whose research provides strong scientific support for the trial, surgeon Dr. Kim who performs the implants, clinician Dr. Meneilly who is an expert in diabetes management, Dr. Levings, a world-renowned immunologist who will monitor patients for immune responses to the implanted cells, Dr. Bubela who will consider regulatory and reimbursement options and patient perspectives, and project leader Dr. Thompson who is the clinical trial site PI and whom will carefully follow the patients. If successful, this clinical trial may lead to the development of a product that can cure millions of patients with diabetes putting an end to insulin injections and making another major accomplishment in Canada’s diabetes research history.
1 avril 2022
31 janvier 2025
2022
Lauralyn McIntyre (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien des essais cliniques
McIntyre
Chercheur principal
Lauralyn McIntyre
999 850
Umbilical Mesenchymal Stem Cells as Cellular Immunotherapy for Septic Shock (UC-CISS): A Phase II RCT
Septic shock is a devastating illness. It is the most severe form of infection and most common reason for admission to the intensive care unit (ICU). It is characterized by a highly dysregulated immune response with cardiovascular collapse and failure of organs and severe repercussions - despite early identification, aggressive resuscitation, and administration of antibiotics, patients with septic shock suffer a seemingly refractory high mortality rate of 20 to 40%, and those who survive face long-term morbidity associated with physical, cognitive, and emotional dysfunction. From a healthcare system perspective, sepsis costs more than 4 billion dollars per year to treat. Despite decades of research, no targeted therapeutic agent for septic shock has improved clinical outcomes. Mesenchymal stromal cells (MSCs) represent an exciting potential therapeutic option as pre-clinical and clinical research suggests that these cells modulate host dysregulated inflammation, reduce energy failure, and enhance pathogen clearance all of which are central to sepsis pathophysiology. Most importantly, MSCs reduce death and restore organ function in septic animal models. Our multi-disciplinary UC-CISS team is the first in the World to have conducted and completed a Phase I clinical trial that evaluated MSCs in septic shock patients. Our trial established that MSCs appear safe and that a Phase II Randomized Controlled Trial (RCT) is feasible. The primary aim of the UC-CISS II RCT is to determine whether 300 million MSCs (highest MSC dose from CISS Phase I) as compared to placebo reduce organ failures defined by an increase of 3 days free from mechanical ventilation, vasopressor agents, or dialysis in 122 patients and 10 academic centres in Canada. Secondary aims will examine safety, death, hospital and ICU length of stay, function and quality of life, and mechanistic actions and biological effects of MSCs in septic shock. A cost-effectiveness analysis will determine whether health benefits gained from MSC therapy justify its additional costs from the perspective of the health care system. Should there be no harm signals with MSCs that are supported by strong evidence for clinical efficacy will provide essential information and justification to proceed to an international Phase III RCT that will be powered for 90-day mortality.
1 avril 2022
31 janvier 2025
2022
Anastasia Tikhonova (P)
University Health Network
Subventions de démarrage pour chercheurs en début de carrière
Tikhonova
Chercheur principal
Anastasia Tikhonova, Courtney Jones
255 750
Targeting the bone marrow microenvironment to promote hematopoietic regeneration
Cancer
Bone marrow niche, hematopoiesis, hematopoietic regeneration, bone marrow microenvironment, hematopoietic stem cell transplantation, metabolism
Outcomes of cancer patients have improved in the past 5 decades due to superior treatments and early detection. Unfortunately, cancer survivors are at increased risk for developing chemotherapy treatment related long-term toxicities including bone damage and dysregulated hematopoiesis. We propose to tackle this problem by interrogating and targeting the effects chemotherapy has on the bone marrow niche. Bone marrow dwelling mesenchymal stem cells support hematopoiesis by maintaining hematopoietic stem cells in this microenvironment. Accumulating evidence points to dysfunctional mesenchymal stem cells underling poor HSC function. Our recent single-cell transcriptomics studies indicate that mesenchymal stem cells differentiation is dysregulated upon exposure to myeloablative chemotherapeutic agent 5-FU. Specifically, MSPCs differentiate into bone marrow adipocytes in response to 5-FU. However, the mechanistic underpinnings of this observation remain elusive. We hypothesis that chemotherapy exposure results in dysregulation of the MSPC differentiation resulting decreased HSC function. Further, retention of normal MSPC differentiation may prevent loss of HSC function. To test this hypothesis, we propose to map the molecular and metabolic consequences of chemotherapy on the bone marrow mesenchymal populations. In addition, we will measure HSC function upon chemotherapy treatment in murine models containing MSPCs that lack the potential to differentiate toward the adipocyte lineage. Our proposed studies – combining physiologically relevant animal models, advanced low input mass-spectrometry based metabolomics analysis, and cutting-edge single-cell genomic methods for the bone marrow niche analysis– have transformative potential to improve the lives of cancer patients.
1 avril 2022
31 janvier 2025
2022
Courtney Jones (C)
University Health Network
Subventions de démarrage pour chercheurs en début de carrière
Tikhonova
Cochercheur
Anastasia Tikhonova, Courtney Jones
44 250
Targeting the bone marrow microenvironment to promote hematopoietic regeneration
Cancer
Bone marrow niche, hematopoiesis, hematopoietic regeneration, bone marrow microenvironment, hematopoietic stem cell transplantation, metabolism
Outcomes of cancer patients have improved in the past 5 decades due to superior treatments and early detection. Unfortunately, cancer survivors are at increased risk for developing chemotherapy treatment related long-term toxicities including bone damage and dysregulated hematopoiesis. We propose to tackle this problem by interrogating and targeting the effects chemotherapy has on the bone marrow niche. Bone marrow dwelling mesenchymal stem cells support hematopoiesis by maintaining hematopoietic stem cells in this microenvironment. Accumulating evidence points to dysfunctional mesenchymal stem cells underling poor HSC function. Our recent single-cell transcriptomics studies indicate that mesenchymal stem cells differentiation is dysregulated upon exposure to myeloablative chemotherapeutic agent 5-FU. Specifically, MSPCs differentiate into bone marrow adipocytes in response to 5-FU. However, the mechanistic underpinnings of this observation remain elusive. We hypothesis that chemotherapy exposure results in dysregulation of the MSPC differentiation resulting decreased HSC function. Further, retention of normal MSPC differentiation may prevent loss of HSC function. To test this hypothesis, we propose to map the molecular and metabolic consequences of chemotherapy on the bone marrow mesenchymal populations. In addition, we will measure HSC function upon chemotherapy treatment in murine models containing MSPCs that lack the potential to differentiate toward the adipocyte lineage. Our proposed studies – combining physiologically relevant animal models, advanced low input mass-spectrometry based metabolomics analysis, and cutting-edge single-cell genomic methods for the bone marrow niche analysis– have transformative potential to improve the lives of cancer patients.
1 avril 2022
31 janvier 2025
2022
Mamatha Bhat (P)
University Health Network
Subventions de démarrage pour chercheurs en début de carrière
Bhat
Chercheur principal
Mamatha Bhat
300 000
A Nanoparticle-based Strategy to Therapeutically Restore Regenerative Capacity in Cirrhotic Livers
Maladies du foie, maladie du foie, maladie hépatique
Chronic liver disease (CLD) affects 1 in 4 Canadians across the spectrum of age and sex, resulting in 5,000 deaths in 2020. Liver transplantation (LT) is offered to patients with end-stage liver disease. However, there were only 564 LTs across Canada in 2020, with 26% of patients dying or dropping off the waiting list due to a lack of donor organs. There is unfortunately no dialysis available to keep patients on the waiting list alive. CLD is often silent, but takes many years to develop cirrhosis due to its ability to regenerate. However, this capacity to regenerate is compromised once the liver transitions from well-compensated to decompensated cirrhosis with portal hypertension complications and liver synthetic dysfunction. The role of the Hippo-YAP pathway is well-known in the control of tissue regeneration. Our preliminary studies shown that fibrotic livers are not as efficient in activating YAP/TAZ signaling, resulting in inefficient liver regeneration PHT. We hypothesize that the Hippo-YAP pathway plays an essential role in fibrotic liver regeneration by activating specific progenitor cells. We will perform and compare single-cell profiling of female and male fibrotic mice following 2/3 hepatectomy to sham-laparotomy controls. Using a network analysis approach, we will characterize signaling pathways driving regeneration even once the liver is scarred. Furthermore, we will characterize the cellular microenvironment of well-compensated cirrhosis patients (specifically non-alcoholic steatohepatitis (NASH) as the most common etiology of CLD), where there remains some regenerative capacity to those who have lost this capacity (decompensated cirrhosis), by Imaging Mass Cytometry. Then, we will combine lipoprotein-like nanoparticles (porphysomes, with high specificity to liver cells) with siRNA targeting the Hippo-WNT-TGF? pathway axis (Tgfbr2, Yap, Taz, and Pcrn) delivered via hydrodynamic tail vein injection as a therapeutic strategy to promote regeneration even once the liver is scarred. The combination of liver-selective lipoprotein-like nanoparticles with siRNA targeting the Hippo-WNT-TGF? pathway axis will represent a novel approach in regenerative medicine, while limiting systemic side effects. Our project will provide the first steps towards a unique therapeutic strategy to rescue defective liver regeneration in patients with CLD.
1 avril 2022
31 janvier 2025
2022
Sheila Teves (P)
University of British Columbia
Subventions de démarrage pour chercheurs en début de carrière
Teves
Chercheur principal
Sheila Teves
300 000
Transcription regulation of hiPSC-derived cardiomyocytes during maturation and hypertrophic cardiomyopathy
Cardiovascular diseases remain the leading cause of death worldwide, despite decades of research and development in therapeutics. A potential limitation in current research approaches is the use of animal models, which do not always recapitulate the physiology, genetic, or molecular mechanisms of cardiovascular diseases in humans. In addition, native cardiac tissue from patients remains a challenge to obtain, and may be complicated by the patient’s history, including co-morbidities and varying responses to different therapeutic interventions. Thus, the development of patient-derived human induced pluripotent stem cells, and their subsequent differentiation into cardiomyocytes (hiPSC-CMs) provide a promising tool to study disease pathology in the individuals with the relevant genetic background. One challenge with hiPSC-CMs, however, is that they fail to fully mature, resembling the immature phenotype in inherited hypertrophic cardiomyopathy, a disease which often does not manifest clinically until post puberty. Therefore, understanding how hiPSC-CMs can be induced to fully mature will not only provide a new tool for development of new therapeutics, but also lead to new insights into disease pathology for hypertrophic cardiomyopathy. The primary goal of this project is to define the molecular mechanisms in hiPSC-CM maturation and identify new targets for hypertrophic cardiomyopathy therapeutics. Towards this goal, we will use a combination of cutting-edge technologies such as (epi)genomics, transcriptomics, and proteomics to dissect the molecular mechanisms governing hiPSC-CM maturation. Specifically, we will examine transcription regulation changes in hiPSC-CM maturation (Aim 1); evaluate the role of mTOR signaling in hiPSC-CM maturation (Aim 2); and investigate the molecular mechanisms involved in hypertrophic cardiomyopathy pathogenesis (Aim 3). This research program will elucidate the earliest events that determine transcription regulation of hiPSC-CM maturation and reveal key mechanisms that contribute to the pathogenesis of hypertrophic cardiomyopathy. Results from this research will further inform the potential of hiPSC-CMs for regenerative medicine therapies as well as for screening potential drug candidates for cardiomyopathies.
1 avril 2022
31 janvier 2025
2022
Amy Wong (P)
Hospital for Sick Children
Subventions de démarrage pour chercheurs en début de carrière
Wong
Chercheur principal
Amy Wong, Bo Wang, Nika Shakiba
135 272
Deciphering cell competition during iPSC differentiation towards lung epithelia
Lung disease is the third leading cause of death worldwide with very limited treatment options for end-stage diseases. Gene therapy is a promising approach for permanent correction of the mutational defect, but delivery of the therapeutic gene to the target cell has proven to be a challenge. Cell-based therapy is an attractive strategy to regenerate diseased airways with cells capable of restoring normal airway function. There are robust differentiation protocols to generate heterogenous airway epithelial cells from iPSC however, the precise mechanism of generating specific cell subtypes remains elusive. To properly regenerate the airways, we need a rigorous understanding of how specific cells emerge from the differentiation process so that these processes can be harnessed for cell-based therapies in the future. In-vitro stem cell differentiations involve precise temporal exposure of the cells to changing morphogens and culture conditions. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. Our goal is to determine how a cell’s fitness dictates cell competition and the emergence of cell progenies during in-vitro pluripotent stem cell (PSC) differentiation towards lung. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. We hypothesize that fitness genes including those that regulate developmental growth and energy metabolism drive cell fate decisions and clonal expansion of elite cells that overcome cell competition. Here, we propose to combine our human pluripotent stem cell (hPSC) differentiation method and newly developed genetic tools to determine how cell fitness influences cell lineage and fate decisions during lung differentiation. We will use simultaneous single cell RNA and targeted DNA sequencing combined with computational modeling and machine deep-learning algorithms to identify fitness genes driving cell competition and lineage outcomes. Our work will shed important insight into engineering elite cells with optimal and controllable fitness characteristics for use in cell-based airway regeneration strategies.
1 avril 2022
31 janvier 2025
2022
Bo Wang (C)
University Health Network
Subventions de démarrage pour chercheurs en début de carrière
Wong
Cochercheur
Amy Wong, Bo Wang, Nika Shakiba
44 625
Deciphering cell competition during iPSC differentiation towards lung epithelia
Lung disease is the third leading cause of death worldwide with very limited treatment options for end-stage diseases. Gene therapy is a promising approach for permanent correction of the mutational defect, but delivery of the therapeutic gene to the target cell has proven to be a challenge. Cell-based therapy is an attractive strategy to regenerate diseased airways with cells capable of restoring normal airway function. There are robust differentiation protocols to generate heterogenous airway epithelial cells from iPSC however, the precise mechanism of generating specific cell subtypes remains elusive. To properly regenerate the airways, we need a rigorous understanding of how specific cells emerge from the differentiation process so that these processes can be harnessed for cell-based therapies in the future. In-vitro stem cell differentiations involve precise temporal exposure of the cells to changing morphogens and culture conditions. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. Our goal is to determine how a cell’s fitness dictates cell competition and the emergence of cell progenies during in-vitro pluripotent stem cell (PSC) differentiation towards lung. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. We hypothesize that fitness genes including those that regulate developmental growth and energy metabolism drive cell fate decisions and clonal expansion of elite cells that overcome cell competition. Here, we propose to combine our human pluripotent stem cell (hPSC) differentiation method and newly developed genetic tools to determine how cell fitness influences cell lineage and fate decisions during lung differentiation. We will use simultaneous single cell RNA and targeted DNA sequencing combined with computational modeling and machine deep-learning algorithms to identify fitness genes driving cell competition and lineage outcomes. Our work will shed important insight into engineering elite cells with optimal and controllable fitness characteristics for use in cell-based airway regeneration strategies.
1 avril 2022
31 janvier 2025
2022
Nika Shakiba (C)
University of British Columbia
Subventions de démarrage pour chercheurs en début de carrière
Wong
Cochercheur
Amy Wong, Bo Wang, Nika Shakiba
120 103
Deciphering cell competition during iPSC differentiation towards lung epithelia
Lung disease is the third leading cause of death worldwide with very limited treatment options for end-stage diseases. Gene therapy is a promising approach for permanent correction of the mutational defect, but delivery of the therapeutic gene to the target cell has proven to be a challenge. Cell-based therapy is an attractive strategy to regenerate diseased airways with cells capable of restoring normal airway function. There are robust differentiation protocols to generate heterogenous airway epithelial cells from iPSC however, the precise mechanism of generating specific cell subtypes remains elusive. To properly regenerate the airways, we need a rigorous understanding of how specific cells emerge from the differentiation process so that these processes can be harnessed for cell-based therapies in the future. In-vitro stem cell differentiations involve precise temporal exposure of the cells to changing morphogens and culture conditions. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. Our goal is to determine how a cell’s fitness dictates cell competition and the emergence of cell progenies during in-vitro pluripotent stem cell (PSC) differentiation towards lung. How these morphogens affect cellular specification and lineage differentiation trajectories remains unknown and how divergent cell types emerge from the same culture condition is also unclear. We hypothesize that fitness genes including those that regulate developmental growth and energy metabolism drive cell fate decisions and clonal expansion of elite cells that overcome cell competition. Here, we propose to combine our human pluripotent stem cell (hPSC) differentiation method and newly developed genetic tools to determine how cell fitness influences cell lineage and fate decisions during lung differentiation. We will use simultaneous single cell RNA and targeted DNA sequencing combined with computational modeling and machine deep-learning algorithms to identify fitness genes driving cell competition and lineage outcomes. Our work will shed important insight into engineering elite cells with optimal and controllable fitness characteristics for use in cell-based airway regeneration strategies.
1 avril 2022
31 janvier 2025
2022
Natasha Chang (P)
Université McGill
Subventions de démarrage pour chercheurs en début de carrière
Duchenne muscular dystrophy (DMD) is a devastating muscle degenerative disease affecting 1 in every 5,000 male births in Canada. DMD manifests in early childhood, as young boys exhibit motor development delays. Progressive weakening of the muscle tissue leads to an inability to walk and patients are wheelchair-bound by age 12. DMD is fatal and patients succumb to death from respiratory and cardiac failure in their 20’s and 30’s. Despite research efforts to understand DMD, there remains no effective cure. Historically, DMD has been viewed as a disease affecting the structural integrity of the muscle tissue, which leads to weakening and damage of the muscle fibers. However, recent studies have shown that muscle stem cells are also affected in DMD. DMD muscle stem cells do not function as normal healthy stem cells and their dysfunction plays a role in disease progression. Importantly, current therapeutic strategies for muscular dystrophy do not address these deficiencies in muscle stem cell function. Our research aims to understand the cellular processes that are altered in DMD muscle stem cells and devise strategies to restore muscle stem cell function to improve muscle repair. In this project, we focus on understanding how autophagy, a metabolic nutrient recycling pathway, regulates muscle stem cell functions. Our data indicate that autophagy in DMD muscle stem cells is dysregulated. Thus, we are examining how impaired muscle stem cell autophagy contributes to DMD pathology. We predict that restoring the autophagy pathway in muscle stem cells will improve dystrophic muscle stem cell function and promote endogenous muscle repair mechanisms in DMD. Our multidisciplinary team is comprised of experts in the field of muscle stem cells and their application to muscle physiology and human disease. The project is led and driven by Natasha Chang, an early career researcher focused on mechanisms of muscle stem cell dysfunction in muscle disease. Essential collaborations to support the this work include Nicolas Dumont (expert in muscle physiology), Pura Muñoz-Canoves (expert in muscle stem cell autophagy) and Bénédicte Chazaud (expert in muscle regeneration and muscular dystrophies). The project will be supported by partners McGill University, McGill Regenerative Medicine Network, Jesse’s Journey, Muscular Dystrophy Canada, and Fonds de recherche du Québec Santé.
1 avril 2022
31 janvier 2025
2022
Nika Shakiba (P)
University of British Columbia
Subventions de démarrage pour chercheurs en début de carrière
Shakiba
Chercheur principal
Nika Shakiba
300 000
Elucidating the competitive advantage of aberrant pluripotent stem cells in suspension bioprocesses
Cell therapies are opening the door to treating degenerative diseases. With ongoing clinical trials, there is accelerating demand for large-scale supply. Human pluripotent stem cells (hPSCs) are a powerful substrate for off-the-shelf cell therapies, owing to their ability to self-renew and differentiate into all cell types of the body. The first step in producing hPSC-derived therapies is expansion, growing billions of hPSCs. However, expansion is plagued by the emergence of genetic variants that acquire favourable, often cancer-associated, genetic changes and render the hPSC batch unsafe for clinical use. Over the past decade, the international stem cell community undertook a collective effort to catalogue common variants but these studies only involve hPSCs in adherent culture. Suspension culture, in which hPSCs grow in small aggregates in stirred bioreactors, has offered a cost-efficient alternative for expansion and now dominates commercial bioprocesses. To ensure that hPSC batches produced by these bioprocesses are high-quality, it is critical that we investigate the growth of variants in suspension. To tackle this unmet need, our central goal is to determine the mechanistic basis by which variants survive and overtake normal hPSCs in commercially-relevant suspension bioprocesses. We will do this by applying a bioengineering approach, combining synthetic biology and mathematical modeling to ask whether: (1) common hPSCs variants experience a selective advantage in suspension; (2) variants aggressively push normal hPSCs out of suspension culture through contact-mediated cell killing, a remarkable phenomenon that was recently uncovered in adherent culture by collaborator Barbaric; and (3) suspension aggregates act as “isolated islands”, where direct contact between variant and normal hPSCs can be controlled by engineering aggregate architecture. As a stem cell bioengineer, my lab has core expertise in pluripotency and the development of genetic tools to track and control stem cells. In an interdisciplinary collaboration with Dr. Ivana Barbaric (hPSC biologist, University of Sheffield) and Dr. Sidhartha Goyal (biophysicist, University of Toronto), we will uncover the mechanistic basis of variant dominance in suspension, providing a foundation for enabling technologies to detect, curb and remove variants and safely manufacture life-saving therapies.
1 avril 2022
31 janvier 2025
2022
Julien Muffat (P)
Hospital for Sick Children
Subventions de démarrage pour chercheurs en début de carrière
Muffat
Chercheur principal
Julien Muffat
300 000
Engineering microglia to support oligodendrocyte transplants, and improve remyelination after white matter injury
Neurological disorders are notoriously difficult to treat, owing to the brain’s inaccessibility and lack of regenerative capacity. Several grave neurological disorders are due to the loss of the insulating sheath protecting nerve bundles. The most prevalent among those disorders is multiple sclerosis (MS). Its causes are still unknown, and MS remains incurable, as neuroinflammation causes brain lesions to progress. In MS, the course can be erratic, but the primary progressive form is inexorably degenerative. A population of brain macrophages, the microglia, may be the root of inflammation. Yet, they can also clear out myelin debris preventing remyelination, and are capable of secreting trophic factors supporting oligodendrocytes. We devised methods to generate such macrophages and oligodendrocytes from patient stem cells. We can let them interact with axons or synthetic fibers, to investigate a reductionist model of myelination. We can also study them in 3D cultures which we call brain avatars. We will use well-established methods to injure oligodendrocytes and study the responses of the tissue, in this uniquely human organotypic model. We will then test transplantation of oligodendrocyte and microglial precursors after injury, as a clinical intervention to re-myelinate the tissue. We predict these cells will jointly engraft, microglia will clear out damaged cells, and unleash powerful regenerative programs targeted towards endogenous and transplanted cells. The advent of pluripotent stem cells gives us an inexhaustible source of patient-matched cells. Genomic engineering will allow us to make designer microglia tailored to specific pathologies. This project will deliver new models that can be screened for therapeutic interventions and will directly test the feasibility of co-transplantation of microglia and oligodendrocyte precursors to improve remyelination outcomes in organotypic human cultures.
1 avril 2022
31 janvier 2025
2022
Ly Vu (P)
University of British Columbia
Subventions de démarrage pour chercheurs en début de carrière
Vu
Chercheur principal
Ly Vu
300 000
Modulating activity of RNA regulating proteins to preserve long-term regenerative potential of Hematopoietic Stem Cells
The clinical use of umbilical cord blood-derived hematopoietic stem cells (CB-HSCs) is key to many regenerative therapies. The treatment is life-saving for many patients living with hematological disorders. However, the broader use of CB-HSC transplantation is still limited mainly due to small supplies of HSCs from a cord blood unit. Therefore, major efforts are aiming at an effective and at-scale expansion of HSCs ex vivo to overcome this bottle neck. While improvement in increasing HSC number has been made, maintenance of the long-term regenerative potential of HSCs remains a complex challenge. Recent works showed that current ex vivo conditions impairs long-term self-renewal of HSCs while supporting generation of progenies with decreased regenerative potential. In culture, activation of HSCs is coupled with induction of cellular stresses, predominantly proteostatic stress characterized by reduced proteome quality in cells. Accumulation of defective proteins impairs HSC’s self-renewal. Therefore, uncovering factors and the molecular circuitry that controls protein homeostasis and stress responses in HSCs will enable the development of effective strategies for both expansion and preservation of HSC potential for regenerative therapies. Here, we identified an RNA binding protein SYNCRIP as a novel player that controls the ability of HSCs to repopulate in serial transplantations. We uncovered that SYNCRIP is required to maintain proteostasis, hence mediating cellular stresses induced by repopulating stressors in HSCs. These results pointed to a central role for SYNCRIP in safeguarding life-long self-renewal capacity of HSCs by controlling protein homeostasis. In this project, we will test the idea that enhancing SYNCRIP’s activity can enable CB-HSCs to overcome proteostatic stresses in the ex vivo culture, thus preserving HSC regenerative potential while allowing expansion of CB-HSCs. We will use cutting-edge technologies to identify SYNCRIP’s functional downstream networks required for HSC self-renewal. The study will provide the basis for development of targeted strategies to improve the functional quality of HSCs during ex vivo expansion for translational and clinical uses. My extensive expertise in RBP biology and hematopoiesis and Dr. Eaves’ pioneering position at the forefront of CB-HSCs research will ensure the success of our team.
1 avril 2022
31 janvier 2025
2022
Daniel Coutu (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de démarrage pour chercheurs en début de carrière
Coutu
Chercheur principal
Daniel Coutu
300 000
Pharmacological rejuvenation of skeletal stem cells for use in regenerative orthopedic surgery
Over 50% of Canadians eventually suffer from musculoskeletal conditions affecting their mobility and quality of life. The regenerative capacity of skeletal tissues declines with age and repeated trauma and can be partially explained by stem cell exhaustion or loss of function. It is therefore important to study the molecular pathways controlling skeletal stem cells (SSCs) fate decision (self-renewal, differentiation, quiescence, senescence, lineage decision) to gain actionable insights towards the development of endogenous or culture-expanded regenerative medicine products. We recently identified two types of SSCs in mice: an osteochondral SSC responsible for bone growth and homeostasis, and a multipotent SSC responsible for joint tissues homeostasis. We showed that human tissues contain similar SSCs, and that skeletal tissues from older and/or arthritic patients contain more senescent cells. We hypothesize that cellular senescence of SSCs or their microenvironment (niche) plays a role in the blunted regenerative capacity of older SSCs and in the development of osteoarthritis. We will test this by performing genetic lineage tracing in animal models of acute of chronic injury and measuring senescence of SSCs. We will then test various drugs for their capacity to enhance tissue repair by stimulating SSCs self-renewal without senescence. Finally, we will test various drugs for their capacity to improve ex vivo expansion of mouse and human SSCs as well as their engraftment in injury models. Our data will provide a biological basis linking stem cell senescence and skeletal tissue re-/degeneration, and proof of concept for pharmacological rejuvenation of SSCs. This project is unique because it bridges fundamental skeletal stem cell biology with translational musculoskeletal research using cutting-edge techniques. It will also pave the way towards pharmacological manipulation of SSCs in human patients. Overall, this project has the potential to improve the quality of life and mobility of millions of suffering Canadians and alleviate the associated socio-economic burden. Our team, composed of world-leading musculoskeletal stem cell biologists and orthopedic surgeons, is uniquely poised to achieve our research objectives, disseminate our results to the community, and develop new regenerative therapies for the benefit of Canadians.
1 avril 2022
31 janvier 2025
2022
Carl de Boer (P)
University of British Columbia
Subventions de démarrage pour chercheurs en début de carrière
Boer
Chercheur principal
Carl de Boer
300 000
Decoding human cis-regulatory logic in development to treat disease
Gene expression programs are largely encoded by cis-regulatory DNA sequence, like promoters and enhancers. These sequences are interpreted by proteins called Transcription Factors (TFs). TFs bind specific sequences in the DNA and work together to interpret DNA sequences. Much of the genetic variation implicated in common complex diseases lies in cis-regulatory regions and is thought to contribute to disease through altered TF binding and consequent changes to gene expression. However, our knowledge of how we go from genotype to disease remains incomplete, in part because it is challenging to accurately predict how genetic variation alters TF binding. If we understood this process in every cell type, we could determine how genetic variation contributes to disease, find ways to counteract genetic risk factors, and even design new cis-regulatory elements that express therapeutic genes in desired ways. We have designed a system that will allow us to create complex models of cis-regulation for any cell type derived from pluripotent stem cells (PSCs). Here, we will measure the expression levels encoded by each of ~10 million random cis-regulatory sequences in each experiment using a high-throughput reporter assay. Using these Big Data, we will create computer models that capture the relationship between DNA sequence and gene expression. We will use these models to predict how genetic variation affects gene expression, enabling us to identify and fix causal genetic risk factors, identify the TFs that are important in the function of cis-regulatory elements, and design cis-regulatory sequences that encode specific regulatory programs. We will develop our approach in two important cell types: PSCs and cardiomyocytes. PSCs are a great starting cell type because experiments are faster and cheaper, enabling optimization. Cardiomyocytes are a great secondary cell type due to their importance in proper cardiac function and disease, and the relative ease of differentiation. By demonstrating our approach in these two cell types, we will enable its widespread use to understand cis-regulation in diverse cell types, facilitating our understanding of the wiring of the cells and enabling regenerative therapies.
1 avril 2022
31 janvier 2025
2022
Maryam Faiz (P)
University of Toronto
Subventions de démarrage pour chercheurs en début de carrière
Faiz
Chercheur principal
Maryam Faiz, Scott Yuzwa, Samer Hussein
154 500
Direct lineage reprogramming of astrocytes to new oligodendrocytes for the treatment of demyelinating disease
The loss or dysfunction of oligodendrocytes (OLs), the myelinating cells in the central nervous system (CNS) is characteristic of many types of neurological disease and injury. Moreover, different types of OLs are lost depending on disease type and severity. Thus, therapeutic strategies aimed at restoring disease specific OLs are of significant clinical interest. Direct lineage reprogramming (DLR), the forced conversion of one cell type to another, is an exciting new technology for CNS repair. However, current DLR strategies have largely focused on the generation of new neurons and there have been almost no studies of OL reprogramming to date. We have successfully converted astrocytes to OLs (iOLs) via the ectopic expression of the transcription factors (TFs) Sox10, Olig2, Nkx6.2. Of interest, delivery of different TFs results in the generation of unique types of iOL lineage cells. A unique aspect of this technology is that in addition to reconstituting functionally important target OL cell populations, DLR can remove donor astrocyte cell types that drive disease progression. With the goal of developing precision therapies that target select pathological astrocyte subtypes and convert them into specific iOL cell types, we will examine the DLR of an A1 astrocyte subtype known to kill oligodendrocytes (Aim 1); investigate human astrocyte to iOL DLR in cerebral organoids (Aim 2); and identify and validate novel factors for iOL conversion in human organoids, and in an animal model of demyelination (Aim 3). Specific deliverables include determining the timeline, efficacy, and type(s) of iOLs generated from A1 astrocytes and in human organoids using Sox10, Olig2 and Nkx6.2; identification of the molecular profiles of human iOLs following DLR; and the identification and validation of factors to improve efficiency and specificity of iOL DLR in vivo and in human organoids. These deliverables will provide go-no-go outcomes for the use of Olig2, Sox10 and Nkx6.2 and other novel targets as human iOL therapeutics, and will be important for demonstrating the feasibility, scope, and therapeutic potential of this approach. Proof-of-principle data will support the foundation of a new company in Toronto to generate new therapeutics for CNS diseases with unmet need, both of benefit to Canadians.
1 avril 2022
31 janvier 2025
2022
Scott Yuzwa (C)
University of Toronto
Subventions de démarrage pour chercheurs en début de carrière
Faiz
Cochercheur
Maryam Faiz, Scott Yuzwa, Samer Hussein
50 500
Direct lineage reprogramming of astrocytes to new oligodendrocytes for the treatment of demyelinating disease
The loss or dysfunction of oligodendrocytes (OLs), the myelinating cells in the central nervous system (CNS) is characteristic of many types of neurological disease and injury. Moreover, different types of OLs are lost depending on disease type and severity. Thus, therapeutic strategies aimed at restoring disease specific OLs are of significant clinical interest. Direct lineage reprogramming (DLR), the forced conversion of one cell type to another, is an exciting new technology for CNS repair. However, current DLR strategies have largely focused on the generation of new neurons and there have been almost no studies of OL reprogramming to date. We have successfully converted astrocytes to OLs (iOLs) via the ectopic expression of the transcription factors (TFs) Sox10, Olig2, Nkx6.2. Of interest, delivery of different TFs results in the generation of unique types of iOL lineage cells. A unique aspect of this technology is that in addition to reconstituting functionally important target OL cell populations, DLR can remove donor astrocyte cell types that drive disease progression. With the goal of developing precision therapies that target select pathological astrocyte subtypes and convert them into specific iOL cell types, we will examine the DLR of an A1 astrocyte subtype known to kill oligodendrocytes (Aim 1); investigate human astrocyte to iOL DLR in cerebral organoids (Aim 2); and identify and validate novel factors for iOL conversion in human organoids, and in an animal model of demyelination (Aim 3). Specific deliverables include determining the timeline, efficacy, and type(s) of iOLs generated from A1 astrocytes and in human organoids using Sox10, Olig2 and Nkx6.2; identification of the molecular profiles of human iOLs following DLR; and the identification and validation of factors to improve efficiency and specificity of iOL DLR in vivo and in human organoids. These deliverables will provide go-no-go outcomes for the use of Olig2, Sox10 and Nkx6.2 and other novel targets as human iOL therapeutics, and will be important for demonstrating the feasibility, scope, and therapeutic potential of this approach. Proof-of-principle data will support the foundation of a new company in Toronto to generate new therapeutics for CNS diseases with unmet need, both of benefit to Canadians.
1 avril 2022
31 janvier 2025
2022
Samer Hussein (C)
University of Toronto
Subventions de démarrage pour chercheurs en début de carrière
Faiz
Cochercheur
Maryam Faiz, Scott Yuzwa, Samer Hussein
95 000
Direct lineage reprogramming of astrocytes to new oligodendrocytes for the treatment of demyelinating disease
The loss or dysfunction of oligodendrocytes (OLs), the myelinating cells in the central nervous system (CNS) is characteristic of many types of neurological disease and injury. Moreover, different types of OLs are lost depending on disease type and severity. Thus, therapeutic strategies aimed at restoring disease specific OLs are of significant clinical interest. Direct lineage reprogramming (DLR), the forced conversion of one cell type to another, is an exciting new technology for CNS repair. However, current DLR strategies have largely focused on the generation of new neurons and there have been almost no studies of OL reprogramming to date. We have successfully converted astrocytes to OLs (iOLs) via the ectopic expression of the transcription factors (TFs) Sox10, Olig2, Nkx6.2. Of interest, delivery of different TFs results in the generation of unique types of iOL lineage cells. A unique aspect of this technology is that in addition to reconstituting functionally important target OL cell populations, DLR can remove donor astrocyte cell types that drive disease progression. With the goal of developing precision therapies that target select pathological astrocyte subtypes and convert them into specific iOL cell types, we will examine the DLR of an A1 astrocyte subtype known to kill oligodendrocytes (Aim 1); investigate human astrocyte to iOL DLR in cerebral organoids (Aim 2); and identify and validate novel factors for iOL conversion in human organoids, and in an animal model of demyelination (Aim 3). Specific deliverables include determining the timeline, efficacy, and type(s) of iOLs generated from A1 astrocytes and in human organoids using Sox10, Olig2 and Nkx6.2; identification of the molecular profiles of human iOLs following DLR; and the identification and validation of factors to improve efficiency and specificity of iOL DLR in vivo and in human organoids. These deliverables will provide go-no-go outcomes for the use of Olig2, Sox10 and Nkx6.2 and other novel targets as human iOL therapeutics, and will be important for demonstrating the feasibility, scope, and therapeutic potential of this approach. Proof-of-principle data will support the foundation of a new company in Toronto to generate new therapeutics for CNS diseases with unmet need, both of benefit to Canadians.
1 avril 2022
31 janvier 2025
2022
Samantha Payne (P)
University of Guelph
Subventions de démarrage pour chercheurs en début de carrière
Payne
Chercheur principal
Samantha Payne
273 775
Investigating neuron-dependent cues to promote tissue regeneration
Scarring, or fibrosis, is the pathological deposition of a collagen I rich matrix and is a common response to injury and inflammation in many tissues and peripheral organs. Scarring is the default response to injury in mammals and leads to a loss of tissue function, however many non-mammalian species are capable of complete restoration in organs such as the heart, brain, and even whole appendages. Successful regeneration requires a complex spatial and temporal coordination of various cells, including the generation of a pool of progenitor cells to replace lost tissue. The presence of peripheral nerves is essential for regeneration, and neural-driven signals direct cell behaviour in the post-injury microenvironment. Specifically, neurotransmitters have been implicated in the recruitment and proliferation of progenitor cells after injury in various organs. However, many of the underlying molecular mechanisms of nerve dependency in regeneration, particularly in mammals, remain unknown. This current lack of mechanistic insight into nerve-dependency hinders the development of potential regenerative medicine therapeutics. The overarching objective of this project is to identify how neural-driven cues mediate the formation of a progenitor cell pool, which will allow us to develop therapeutic strategies to promote regeneration. One of the main challenges in studying the role of nerves in model organisms is the complexity of the microenvironment. To address this, our approach consists of the complementary use of both mammalian (scarring) and non-mammalian (regeneration-competent) cells in an in vitro model combined with an in vivo model of digit tip regeneration. This project has three main objectives: 1) Establish and characterize progenitor cell populations following injury, 2) Identify the nerve-dependent signalling that maintains progenitor cell status, and 3) Determine the role of neurotransmitters in promoting regeneration. Completion of these objectives will provide foundational knowledge about the key drivers of regeneration, bridging the gap between regenerative biology and medicine to develop targeted therapeutics to promote regeneration across different tissues and organs.
1 avril 2022
31 janvier 2025
2022
Shinichiro Ogawa (P)
University Health Network
Subventions de soutien aux partenariats biotechnologiques
Ogawa
Chercheur principal
Shinichiro Ogawa, Gordon Keller, Ian McGilvray, Sonya MacParland
331 500
Developing functional 3D bioprinted liver tissues with sustained immune evasion
Maladies du foie, maladie du foie, maladie hépatique
3D bioprinting, Human pluripotent stem cells, Hepatocytes, Immune suppression, Liver tissues
Human pluripotent stem cell-derived hepatocyte (hPSC-hep) transplantation is an exciting alternative approach to whole organ replacement for restoring liver function. Successful clinical transplantation of hPSC-heps requires overcoming immune rejection and delivering a sufficient cell to restore liver function. Our team, led by Shin Ogawa (McEwen Stem Cell Institute), will leverage expertise in stem cell biology, immunology, liver transplantation, and bioprinting (Aspect Biosystems Ltd.) to develop a safe clinical-grade product to treat end-stage liver failure. The objective of this project is to optimize a scalable, immune-protected liver cell replacement tissue by 1) generating sufficient numbers of functional liver cells (hepatocytes) using hPSCs, 2) encapsulating therapeutic doses of hPSC-heps using a novel 3D bioprinting approach, and 3) ex vivo gene editing of immune-modulatory genes in hPSCs to further protect the graft from immune system attack. We have developed a protocol for the efficient generation of hPSC-derived hepatocytes and identified several new regulatory factors that promote the maturation of these cells to a stage comparable to the human adult liver. Our protocols to serially expand hPSC-derived hepatocyte progenitors and successfully cryopreserve them will enable further expansion and maturation of these cells for implantation. Aspect Biosystems’ microfluidic-based 3D bioprinting technology can generate implantable tissues containing fragile cell types including primary human hepatocytes, with high cell viability and function in vivo. Aspect’s system can surround cells with an outer layer of selectively permeable biomaterials to shield allogeneic therapeutic cells from host immune attack, thereby avoiding the requirement for patient immune suppression. The proposed pre-clinical studies will combine our hPSC-hep differentiation protocols with immune-evading, bioprinted tissue technologies. These optimization studies will guide the development of scalable manufacturing strategies for large-scale production of immune-evading hepatocytes for implantation and advance developments towards clinical trials. Our project will establish a foundation for developing commercial bioprinted hepatocyte-based therapies to improve the lives of Canadians suffering from acute liver failure and end-stage liver diseases.
1 avril 2022
31 mars 2024
2022
Gordon Keller (C)
University Health Network
Subventions de soutien aux partenariats biotechnologiques
Ogawa
Cochercheur
Shinichiro Ogawa, Gordon Keller, Ian McGilvray, Sonya MacParland
5 000
Developing functional 3D bioprinted liver tissues with sustained immune evasion
Maladies du foie, maladie du foie, maladie hépatique
3D bioprinting, Human pluripotent stem cells, Hepatocytes, Immune suppression, Liver tissues
Human pluripotent stem cell-derived hepatocyte (hPSC-hep) transplantation is an exciting alternative approach to whole organ replacement for restoring liver function. Successful clinical transplantation of hPSC-heps requires overcoming immune rejection and delivering a sufficient cell to restore liver function. Our team, led by Shin Ogawa (McEwen Stem Cell Institute), will leverage expertise in stem cell biology, immunology, liver transplantation, and bioprinting (Aspect Biosystems Ltd.) to develop a safe clinical-grade product to treat end-stage liver failure. The objective of this project is to optimize a scalable, immune-protected liver cell replacement tissue by 1) generating sufficient numbers of functional liver cells (hepatocytes) using hPSCs, 2) encapsulating therapeutic doses of hPSC-heps using a novel 3D bioprinting approach, and 3) ex vivo gene editing of immune-modulatory genes in hPSCs to further protect the graft from immune system attack. We have developed a protocol for the efficient generation of hPSC-derived hepatocytes and identified several new regulatory factors that promote the maturation of these cells to a stage comparable to the human adult liver. Our protocols to serially expand hPSC-derived hepatocyte progenitors and successfully cryopreserve them will enable further expansion and maturation of these cells for implantation. Aspect Biosystems’ microfluidic-based 3D bioprinting technology can generate implantable tissues containing fragile cell types including primary human hepatocytes, with high cell viability and function in vivo. Aspect’s system can surround cells with an outer layer of selectively permeable biomaterials to shield allogeneic therapeutic cells from host immune attack, thereby avoiding the requirement for patient immune suppression. The proposed pre-clinical studies will combine our hPSC-hep differentiation protocols with immune-evading, bioprinted tissue technologies. These optimization studies will guide the development of scalable manufacturing strategies for large-scale production of immune-evading hepatocytes for implantation and advance developments towards clinical trials. Our project will establish a foundation for developing commercial bioprinted hepatocyte-based therapies to improve the lives of Canadians suffering from acute liver failure and end-stage liver diseases.
1 avril 2022
31 mars 2024
2022
Ian McGilvray (C)
University Health Network
Subventions de soutien aux partenariats biotechnologiques
Ogawa
Cochercheur
Shinichiro Ogawa, Gordon Keller, Ian McGilvray, Sonya MacParland
23 750
Developing functional 3D bioprinted liver tissues with sustained immune evasion
Maladies du foie, maladie du foie, maladie hépatique
3D bioprinting, Human pluripotent stem cells, Hepatocytes, Immune suppression, Liver tissues
Human pluripotent stem cell-derived hepatocyte (hPSC-hep) transplantation is an exciting alternative approach to whole organ replacement for restoring liver function. Successful clinical transplantation of hPSC-heps requires overcoming immune rejection and delivering a sufficient cell to restore liver function. Our team, led by Shin Ogawa (McEwen Stem Cell Institute), will leverage expertise in stem cell biology, immunology, liver transplantation, and bioprinting (Aspect Biosystems Ltd.) to develop a safe clinical-grade product to treat end-stage liver failure. The objective of this project is to optimize a scalable, immune-protected liver cell replacement tissue by 1) generating sufficient numbers of functional liver cells (hepatocytes) using hPSCs, 2) encapsulating therapeutic doses of hPSC-heps using a novel 3D bioprinting approach, and 3) ex vivo gene editing of immune-modulatory genes in hPSCs to further protect the graft from immune system attack. We have developed a protocol for the efficient generation of hPSC-derived hepatocytes and identified several new regulatory factors that promote the maturation of these cells to a stage comparable to the human adult liver. Our protocols to serially expand hPSC-derived hepatocyte progenitors and successfully cryopreserve them will enable further expansion and maturation of these cells for implantation. Aspect Biosystems’ microfluidic-based 3D bioprinting technology can generate implantable tissues containing fragile cell types including primary human hepatocytes, with high cell viability and function in vivo. Aspect’s system can surround cells with an outer layer of selectively permeable biomaterials to shield allogeneic therapeutic cells from host immune attack, thereby avoiding the requirement for patient immune suppression. The proposed pre-clinical studies will combine our hPSC-hep differentiation protocols with immune-evading, bioprinted tissue technologies. These optimization studies will guide the development of scalable manufacturing strategies for large-scale production of immune-evading hepatocytes for implantation and advance developments towards clinical trials. Our project will establish a foundation for developing commercial bioprinted hepatocyte-based therapies to improve the lives of Canadians suffering from acute liver failure and end-stage liver diseases.
1 avril 2022
31 mars 2024
2022
Sonya MacParland (C)
University Health Network
Subventions de soutien aux partenariats biotechnologiques
Ogawa
Cochercheur
Shinichiro Ogawa, Gordon Keller, Ian McGilvray, Sonya MacParland
39 750
Developing functional 3D bioprinted liver tissues with sustained immune evasion
Maladies du foie, maladie du foie, maladie hépatique
3D bioprinting, Human pluripotent stem cells, Hepatocytes, Immune suppression, Liver tissues
Human pluripotent stem cell-derived hepatocyte (hPSC-hep) transplantation is an exciting alternative approach to whole organ replacement for restoring liver function. Successful clinical transplantation of hPSC-heps requires overcoming immune rejection and delivering a sufficient cell to restore liver function. Our team, led by Shin Ogawa (McEwen Stem Cell Institute), will leverage expertise in stem cell biology, immunology, liver transplantation, and bioprinting (Aspect Biosystems Ltd.) to develop a safe clinical-grade product to treat end-stage liver failure. The objective of this project is to optimize a scalable, immune-protected liver cell replacement tissue by 1) generating sufficient numbers of functional liver cells (hepatocytes) using hPSCs, 2) encapsulating therapeutic doses of hPSC-heps using a novel 3D bioprinting approach, and 3) ex vivo gene editing of immune-modulatory genes in hPSCs to further protect the graft from immune system attack. We have developed a protocol for the efficient generation of hPSC-derived hepatocytes and identified several new regulatory factors that promote the maturation of these cells to a stage comparable to the human adult liver. Our protocols to serially expand hPSC-derived hepatocyte progenitors and successfully cryopreserve them will enable further expansion and maturation of these cells for implantation. Aspect Biosystems’ microfluidic-based 3D bioprinting technology can generate implantable tissues containing fragile cell types including primary human hepatocytes, with high cell viability and function in vivo. Aspect’s system can surround cells with an outer layer of selectively permeable biomaterials to shield allogeneic therapeutic cells from host immune attack, thereby avoiding the requirement for patient immune suppression. The proposed pre-clinical studies will combine our hPSC-hep differentiation protocols with immune-evading, bioprinted tissue technologies. These optimization studies will guide the development of scalable manufacturing strategies for large-scale production of immune-evading hepatocytes for implantation and advance developments towards clinical trials. Our project will establish a foundation for developing commercial bioprinted hepatocyte-based therapies to improve the lives of Canadians suffering from acute liver failure and end-stage liver diseases.
1 avril 2022
31 mars 2024
2022
Michael Underhill (P)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Underhill
Chercheur principal
Michael Underhill, Pamela Hoodless
324 200
Novel therapeutic strategies to promote liver regeneration
Maladies du foie, maladie du foie, maladie hépatique
Mesenchymal progenitors (MPs) are found in every tissue and figure prominently in health and disease. At homeostasis, MPs are quiescent and transition to an "activated" myofibroblast-like state in response to injury (or other signals). Under these conditions, they produce a transient microenvironment to support tissue regeneration, whereas in repair, they persist and directly contribute to tissue scarring and fibrosis. Fibrosis underlies most chronic disease and is a major contributor to end-stage organ failure. In some instances, removal of the injurious agent is accompanied by significant disease regression and the re-appearance of “quiescent” liver MPs (termed hepatic stellate cells, HSCs). To study MP biology, we generated Hypermethylated in Cancer 1 (Hic1)-based genetic tools, and recently showed that HIC1 regulates MP quiescence. Hic1 will be used as a proxy of HSC quiescence to develop new therapeutic strategies aimed at promoting HSC quiescence and/or inactivation, supporting the restoration of liver function in disease. In this manner, agents that restore HSC quiescence are expected to break the cycle of pathological HSC activation. This grant will utilize a pre-clinical paradigm to identify and evaluate HSC quiescence-modifying compounds as a novel therapeutic strategy to enhance endogenous liver regeneration. Objectives: 1) Identify HSC-quiescence inducing candidates, 2) assess the activity of novel HSC modulators in liver regeneration and 3) file methods of use patents. Deliverables: 1) Therapeutically tractable strategies to manipulate HSC quiescence and/or activation state to affect liver regeneration; 2) new intellectual property to support commercialization. Originality/Innovation: This application builds on unique insights into MP biology gained through the analysis of novel genetic tools across multiple regeneration models, and fundamental insights into MP fate and function in regeneration. Economic, health and social benefit: The resulting IP will be used to support commercialization efforts through existing start-ups and/or out-licensing. Methods to enhance liver regeneration will have enormous health and quality of life benefits for the treatment of liver disease. Team: Hoodless (BCCRC) and Underhill (UBC) groups have a history of collaboration on MP biology, which we are now expanding to focus on MPs in liver regeneration.
1 avril 2022
31 mars 2024
2022
Pamela Hoodless (C)
BC Cancer, part of the Provincial Health Services Authority
Subventions de soutien aux partenariats biotechnologiques
Underhill
Cochercheur
Michael Underhill, Pamela Hoodless
75 000
Novel therapeutic strategies to promote liver regeneration
Maladies du foie, maladie du foie, maladie hépatique
Mesenchymal progenitors (MPs) are found in every tissue and figure prominently in health and disease. At homeostasis, MPs are quiescent and transition to an "activated" myofibroblast-like state in response to injury (or other signals). Under these conditions, they produce a transient microenvironment to support tissue regeneration, whereas in repair, they persist and directly contribute to tissue scarring and fibrosis. Fibrosis underlies most chronic disease and is a major contributor to end-stage organ failure. In some instances, removal of the injurious agent is accompanied by significant disease regression and the re-appearance of “quiescent” liver MPs (termed hepatic stellate cells, HSCs). To study MP biology, we generated Hypermethylated in Cancer 1 (Hic1)-based genetic tools, and recently showed that HIC1 regulates MP quiescence. Hic1 will be used as a proxy of HSC quiescence to develop new therapeutic strategies aimed at promoting HSC quiescence and/or inactivation, supporting the restoration of liver function in disease. In this manner, agents that restore HSC quiescence are expected to break the cycle of pathological HSC activation. This grant will utilize a pre-clinical paradigm to identify and evaluate HSC quiescence-modifying compounds as a novel therapeutic strategy to enhance endogenous liver regeneration. Objectives: 1) Identify HSC-quiescence inducing candidates, 2) assess the activity of novel HSC modulators in liver regeneration and 3) file methods of use patents. Deliverables: 1) Therapeutically tractable strategies to manipulate HSC quiescence and/or activation state to affect liver regeneration; 2) new intellectual property to support commercialization. Originality/Innovation: This application builds on unique insights into MP biology gained through the analysis of novel genetic tools across multiple regeneration models, and fundamental insights into MP fate and function in regeneration. Economic, health and social benefit: The resulting IP will be used to support commercialization efforts through existing start-ups and/or out-licensing. Methods to enhance liver regeneration will have enormous health and quality of life benefits for the treatment of liver disease. Team: Hoodless (BCCRC) and Underhill (UBC) groups have a history of collaboration on MP biology, which we are now expanding to focus on MPs in liver regeneration.
1 avril 2022
31 mars 2024
2022
Guy Sauvageau (P)
Université de Montréal
Subventions du programme Horizon
Sauvageau
Chercheur principal
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
1 282 964
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Etienne Gagnon (C)
Université de Montréal
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
625 110
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Josée Hébert (C)
Hôpital Maisoneuve-Rosemont, centre de recherche
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
140 000
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Ma'n Zawati (C)
Université McGill
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
124 926
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Peter Zandstra (C)
University of British Columbia
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
157 500
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Nika Shakiba (C)
University of British Columbia
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
75 000
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
April 1, 2022
January 31, 2025
2022
Philippe Roux (C)
Université de Montréal
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
117 500
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
Vincent-Philippe Lavallée (C)
Centre Hospitalier Universitaire Sainte-Justine
Subventions du programme Horizon
Sauvageau
Cochercheur
Guy Sauvageau, Etienne Gagnon, Josée Hébert, Ma'n Zawati, Peter Zandstra, Nika Shakiba, Philippe Roux, Vincent-Philippe Lavallée
477 000
Engineered hematopoietic stem cells (eHSCs) as vehicles for next generation therapies
The low regenerative capacity of chimeric antigen receptor (CAR)-expressing T and NK cells remains one of the major barriers to cellular immunotherapies. CAR T/NK cells, like therapeutic antibody derivatives are designed to target cancer-specific cell-surface epitopes of relapsed/refractory hematologic malignancies. However, the lack of surface epitopes amenable to antibody- or CAR-based immuno-therapies for myeloid neoplasms like AML remains an obstacle since such antigens are largely shared with normal hematopoietic stem cells (HSCs). This has prohibitive implications for therapy success because of toxicities against normal HSCs. Furthermore, current CAR technologies suffer from severe side-effects like cytokine-release-syndrome (CRS) and limited persistence of CAR cells in patients, ultimately impacting long-term suppression of relapse-causing cancer cells leading to high treatment costs and limiting more universal access for patients. Five aims are proposed to approach this problem: (1) Identify prime therapy-relevant surface epitopes expressed in AML based on integrated analysis of surface-proteomic, single-cell and normal tissue expression databases. (2) Functionally assess these surface epitopes to identify candidates whose expression is dispensable for normal HSCs and downstream lineages using systematic gene knock-down studies. (3) Identify immunotherapeutic agents against surface epitope combinations based on their ability to eradicate AML cells while sparing normal HSCs that have been genetically engineered for reduced antigen expression. (4) Development of engineered HSC grafts designed to drive long-term and lineage-selective expression of a new generation of modular CARs in immune effector cells to achieve improved efficiency and reduced off-target toxicity in patients. (5) Position this technology for clinical translation in Canada by addressing key socio-economical and regulatory issues. In summary, our proposal leverages key expertise from members of our Canadian and international team to combine the power of regenerative medicine (engineered HSC therapy) to significantly enhance therapeutic antibody and CAR-based technologies (targeting AML or selective AML subclasses, improved on-target activity, etc.) and provide a long-lasting solution for high-risk disease patients that are not curable under current medicine.
1 avril 2022
31 janvier 2025
2022
James Shapiro (P)
University of Alberta
Subventions du programme Horizon
Shapiro
Chercheur principal
James Shapiro, Michael Kallos, Nika Shakiba, Timothy Kieffer
2 450 238
Autologous iPSC-Islets for Personalized Diabetes Therapy: a First-in-Human Implantation and Scale-up Manufacturing
Diabetes results from the lack of insulin, a hormone released by the islet cells in the pancreas to control blood sugar, leading to serious complications. Islet transplant has been a successful therapy; however, life-long immune suppression and shortage of donor organs make it suitable only for a subpopulation of people with ‘brittle’ diabetes. Our vision is to cure diabetes by replacing the damaged islets with new cells manufactured from their own blood reprogrammed into inducible pluripotent stem cells (iPSC). Being ‘self’-derived, these cells will be accepted by the immune system without anti-rejection drugs. Being able to transplant an unlimited supply of autologous islets without immunosuppressants is a novel approach to treat diabetes and could be the world’s first functional cure. Shapiro lab and others have generated iPSC from patients’ blood and differentiated them in mini bioreactors into insulin-producing islets, which successfully reversed diabetes when transplanted in mice. Here we aim to advance this potential into a curative treatment that is safe, effective, mass-producible, and economically and socially viable. We have assembled an interdisciplinary team in stem cell and islet biology, transplant surgery, and bioengineering to deliver our objectives: 1) to generate small-scale, GMP-grade iPSC-islet products from people with diabetes, and implant them subcutaneously to evaluate their safety and preliminary efficacy; 2) to scale up iPSC-islet manufacturing to therapeutic doses using large capacity bioreactors and 3) to validate the product using in vitro and in vivo models. Within 3 years, we expect to provide a proof-of-concept that autologous iPSC-islets 1) are safe and effective for transplantation in humans and 2) can be manufactured in a scalable dose with realistic cost. In 5 years, we expect to move into a scale-up GMP manufacturing of iPSC-islet products for a transplantation trial following regulatory approval, leading to a protected IP and industry manufacturing in 10 years.
1 avril 2022
31 janvier 2025
2022
Michael Kallos (C)
University of Calgary
Subventions du programme Horizon
Shapiro
Cochercheur
Michael Kallos, Nika Shakiba, Timothy Kieffer, Sara Vasconcelos
298 825
Autologous iPSC-Islets for Personalized Diabetes Therapy: a First-in-Human Implantation and Scale-up Manufacturing
Diabetes results from the lack of insulin, a hormone released by the islet cells in the pancreas to control blood sugar, leading to serious complications. Islet transplant has been a successful therapy; however, life-long immune suppression and shortage of donor organs make it suitable only for a subpopulation of people with ‘brittle’ diabetes. Our vision is to cure diabetes by replacing the damaged islets with new cells manufactured from their own blood reprogrammed into inducible pluripotent stem cells (iPSC). Being ‘self’-derived, these cells will be accepted by the immune system without anti-rejection drugs. Being able to transplant an unlimited supply of autologous islets without immunosuppressants is a novel approach to treat diabetes and could be the world’s first functional cure. Shapiro lab and others have generated iPSC from patients’ blood and differentiated them in mini bioreactors into insulin-producing islets, which successfully reversed diabetes when transplanted in mice. Here we aim to advance this potential into a curative treatment that is safe, effective, mass-producible, and economically and socially viable. We have assembled an interdisciplinary team in stem cell and islet biology, transplant surgery, and bioengineering to deliver our objectives: 1) to generate small-scale, GMP-grade iPSC-islet products from people with diabetes, and implant them subcutaneously to evaluate their safety and preliminary efficacy; 2) to scale up iPSC-islet manufacturing to therapeutic doses using large capacity bioreactors and 3) to validate the product using in vitro and in vivo models. Within 3 years, we expect to provide a proof-of-concept that autologous iPSC-islets 1) are safe and effective for transplantation in humans and 2) can be manufactured in a scalable dose with realistic cost. In 5 years, we expect to move into a scale-up GMP manufacturing of iPSC-islet products for a transplantation trial following regulatory approval, leading to a protected IP and industry manufacturing in 10 years.
1 avril 2022
31 janvier 2025
2022
Timothy Kieffer (C)
University of British Columbia
Subventions du programme Horizon
Shapiro
Cochercheur
Timothy Kieffer, Sara Vasconcelos, Gregory Korbutt, Michael Laflamme
244 333
Autologous iPSC-Islets for Personalized Diabetes Therapy: a First-in-Human Implantation and Scale-up Manufacturing
Diabetes results from the lack of insulin, a hormone released by the islet cells in the pancreas to control blood sugar, leading to serious complications. Islet transplant has been a successful therapy; however, life-long immune suppression and shortage of donor organs make it suitable only for a subpopulation of people with ‘brittle’ diabetes. Our vision is to cure diabetes by replacing the damaged islets with new cells manufactured from their own blood reprogrammed into inducible pluripotent stem cells (iPSC). Being ‘self’-derived, these cells will be accepted by the immune system without anti-rejection drugs. Being able to transplant an unlimited supply of autologous islets without immunosuppressants is a novel approach to treat diabetes and could be the world’s first functional cure. Shapiro lab and others have generated iPSC from patients’ blood and differentiated them in mini bioreactors into insulin-producing islets, which successfully reversed diabetes when transplanted in mice. Here we aim to advance this potential into a curative treatment that is safe, effective, mass-producible, and economically and socially viable. We have assembled an interdisciplinary team in stem cell and islet biology, transplant surgery, and bioengineering to deliver our objectives: 1) to generate small-scale, GMP-grade iPSC-islet products from people with diabetes, and implant them subcutaneously to evaluate their safety and preliminary efficacy; 2) to scale up iPSC-islet manufacturing to therapeutic doses using large capacity bioreactors and 3) to validate the product using in vitro and in vivo models. Within 3 years, we expect to provide a proof-of-concept that autologous iPSC-islets 1) are safe and effective for transplantation in humans and 2) can be manufactured in a scalable dose with realistic cost. In 5 years, we expect to move into a scale-up GMP manufacturing of iPSC-islet products for a transplantation trial following regulatory approval, leading to a protected IP and industry manufacturing in 10 years.
1 avril 2022
31 janvier 2025
2022
Sara Vasconcelos (P)
University Health Network
Subventions du programme Horizon
Vasconcelos
Chercheur principal
Sara Vasconcelos, Gregory Korbutt, Michael Laflamme
2 270 110
Advancing microvessel-based cardiac regeneration into a large pre-clinical animal model
Myocardial infarction (MI) is one of the most prevalent types of cardiac disease with a significant burden for the health care system. A potential cure for MI lies in cell-based therapies in which human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are transplanted to the infarcted area to replace the CMs lost during MI. This, however, yields only modest improvements in cardiac function as a result of the massive death of implanted CMs due to ischemia. Using a rat model of MI, we have demonstrated that ready-made microvessels (MVs) promote the survival of implanted hPSC-CMs by providing early blood perfusion into the graft, resulting in cardiac function recovery. Moreover, MVs show unprecedented retention – overcoming a major bottleneck in cell-based revascularization therapies. Therefore, we are uniquely poised to advance this revascularization strategy into a large animal model that will provide essential efficacy and safety data on the application of MVs in infarcted cardiac therapy before this technology can be moved into clinical trials. In this project, we will study the effectiveness of our MV technology in a more clinically relevant large animal model of MI (pig). Our study will deliver an effective vascularization approach for the ischemic myocardium. Our hypothesis is that the early perfusion provided by the microvessels will enable meaningful cardiac remuscularization and will decrease hiPSC-CM-induced arrhythmias. This work addresses a major obstacle in cell-replacement therapies and builds on our extensive collective expertise on MV isolation and transplantation (Vasconcelos), CM transplantation and graft evaluation in large animal models (Laflamme), state-of-the-art non-invasive imaging of heart function and perfusion (Ghugre) and development of Good Manufacturing Practice compliant protocols (Korbutt) as well as partnership with Advanced Solutions Life Sciences (USA). We have exciting data demonstrating the potential of the technology in a rodent model and our team has the necessary expertise to support the feasibility of these studies. Importantly, given that revascularization is a major bottleneck for regenerative medicine in any organ, this project has the potential to advance cell replacement therapies in multiple organs.
1 avril 2022
31 janvier 2025
2022
Gregory Korbutt (C)
University of Alberta
Subventions du programme Horizon
Vasconcelos
Cochercheur
Sara Vasconcelos, Gregory Korbutt, Michael Laflamme
100 800
Advancing microvessel-based cardiac regeneration into a large pre-clinical animal model
Myocardial infarction (MI) is one of the most prevalent types of cardiac disease with a significant burden for the health care system. A potential cure for MI lies in cell-based therapies in which human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are transplanted to the infarcted area to replace the CMs lost during MI. This, however, yields only modest improvements in cardiac function as a result of the massive death of implanted CMs due to ischemia. Using a rat model of MI, we have demonstrated that ready-made microvessels (MVs) promote the survival of implanted hPSC-CMs by providing early blood perfusion into the graft, resulting in cardiac function recovery. Moreover, MVs show unprecedented retention – overcoming a major bottleneck in cell-based revascularization therapies. Therefore, we are uniquely poised to advance this revascularization strategy into a large animal model that will provide essential efficacy and safety data on the application of MVs in infarcted cardiac therapy before this technology can be moved into clinical trials. In this project, we will study the effectiveness of our MV technology in a more clinically relevant large animal model of MI (pig). Our study will deliver an effective vascularization approach for the ischemic myocardium. Our hypothesis is that the early perfusion provided by the microvessels will enable meaningful cardiac remuscularization and will decrease hiPSC-CM-induced arrhythmias. This work addresses a major obstacle in cell-replacement therapies and builds on our extensive collective expertise on MV isolation and transplantation (Vasconcelos), CM transplantation and graft evaluation in large animal models (Laflamme), state-of-the-art non-invasive imaging of heart function and perfusion (Ghugre) and development of Good Manufacturing Practice compliant protocols (Korbutt) as well as partnership with Advanced Solutions Life Sciences (USA). We have exciting data demonstrating the potential of the technology in a rodent model and our team has the necessary expertise to support the feasibility of these studies. Importantly, given that revascularization is a major bottleneck for regenerative medicine in any organ, this project has the potential to advance cell replacement therapies in multiple organs.
1 avril 2022
31 janvier 2025
2022
Michael Laflamme (C)
University Health Network
Subventions du programme Horizon
Vasconcelos
Cochercheur
Sara Vasconcelos, Gregory Korbutt, Michael Laflamme
629 090
Advancing microvessel-based cardiac regeneration into a large pre-clinical animal model
Myocardial infarction (MI) is one of the most prevalent types of cardiac disease with a significant burden for the health care system. A potential cure for MI lies in cell-based therapies in which human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are transplanted to the infarcted area to replace the CMs lost during MI. This, however, yields only modest improvements in cardiac function as a result of the massive death of implanted CMs due to ischemia. Using a rat model of MI, we have demonstrated that ready-made microvessels (MVs) promote the survival of implanted hPSC-CMs by providing early blood perfusion into the graft, resulting in cardiac function recovery. Moreover, MVs show unprecedented retention – overcoming a major bottleneck in cell-based revascularization therapies. Therefore, we are uniquely poised to advance this revascularization strategy into a large animal model that will provide essential efficacy and safety data on the application of MVs in infarcted cardiac therapy before this technology can be moved into clinical trials. In this project, we will study the effectiveness of our MV technology in a more clinically relevant large animal model of MI (pig). Our study will deliver an effective vascularization approach for the ischemic myocardium. Our hypothesis is that the early perfusion provided by the microvessels will enable meaningful cardiac remuscularization and will decrease hiPSC-CM-induced arrhythmias. This work addresses a major obstacle in cell-replacement therapies and builds on our extensive collective expertise on MV isolation and transplantation (Vasconcelos), CM transplantation and graft evaluation in large animal models (Laflamme), state-of-the-art non-invasive imaging of heart function and perfusion (Ghugre) and development of Good Manufacturing Practice compliant protocols (Korbutt) as well as partnership with Advanced Solutions Life Sciences (USA). We have exciting data demonstrating the potential of the technology in a rodent model and our team has the necessary expertise to support the feasibility of these studies. Importantly, given that revascularization is a major bottleneck for regenerative medicine in any organ, this project has the potential to advance cell replacement therapies in multiple organs.
1 avril 2022
31 janvier 2025
2022
Juan Carlos Zúñiga-Pflücker (C)
Sunnybrook Health Sciences Centre
Subventions de soutien aux projects à fort impact
Keller
Cochercheur
Gordon Keller
Juan Carlos Zúñiga-Pflücker
100 000
Novel human pluripotent stem cell-derived hematopoietic cell therapy
Multiples maladies
Human pluripotent stem cells, hematopoietic stem cells, T cell progenitors, neutrophil progenitors, cell therapy
The ability to generate functional hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSC) provides a platform for developing novel cell-based therapies for a number of different hematological disorders. While this opportunity has been recognized for some time, progress toward this goal has been severely hampered by the poor engraftment potential of hPSC-derived blood progenitors generated to date. To overcome this challenge, the Keller lab has developed a novel differentiation protocol that promotes the development of CD34+ populations that display multilineage engraftment in NSG mice. With these advances, we believe it is now possible to regenerate the entire hematopoietic system with hPSC-derived progenitors. The goals of the studies in this proposal are to generate hPSC-derived CD34+ progenitors that can provide: i) long-term multilineage engraftment and ii) medium- to long-term T cell engraftment. Long-term multilineage engraftment would indicate that we have succeeded in generating HSCs from hPSCs. HPSC-derived HSCs would represent an alternate source of these cells for patients that do not have a matched donor. Engraftment of T-cell lineage restricted progenitors would provide a novel approach for regenerating functional immune cells in immune deficient patients or in bone marrow transplant patients with delayed T cell regeneration. We propose to achieve these goals in the following 2 aims: In Aim 1, we will characterize in detail the long-term, multilineage engraftment potential of the definitive hPSC-derived progenitors. In Aim 2, we will evaluate the engraftment potential of T cell progenitors generated from the hPSC-derived definitive CD34+ progenitors. The findings from these studies have the potential to dramatically impact bone marrow transplantation therapy as they will provide the information necessary for designing stem/progenitor cell grafts that will rapidly restore critical immune functions in transplant patients together with long-term hematopoietic engraftment.
1 avril 2022
31 mars 2024
2022
Gordon Keller (P)
University Health Network
Subventions de soutien aux projects à fort impact
Keller
Chercheur principal
Gordon Keller, Juan Carlos Zúñiga-Pflücker
149 820
Novel human pluripotent stem cell-derived hematopoietic cell therapy
Multiples maladies
Human pluripotent stem cells, hematopoietic stem cells, T cell progenitors, neutrophil progenitors, cell therapy
The ability to generate functional hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSC) provides a platform for developing novel cell-based therapies for a number of different hematological disorders. While this opportunity has been recognized for some time, progress toward this goal has been severely hampered by the poor engraftment potential of hPSC-derived blood progenitors generated to date. To overcome this challenge, the Keller lab has developed a novel differentiation protocol that promotes the development of CD34+ populations that display multilineage engraftment in NSG mice. With these advances, we believe it is now possible to regenerate the entire hematopoietic system with hPSC-derived progenitors. The goals of the studies in this proposal are to generate hPSC-derived CD34+ progenitors that can provide: i) long-term multilineage engraftment and ii) medium- to long-term T cell engraftment. Long-term multilineage engraftment would indicate that we have succeeded in generating HSCs from hPSCs. HPSC-derived HSCs would represent an alternate source of these cells for patients that do not have a matched donor. Engraftment of T-cell lineage restricted progenitors would provide a novel approach for regenerating functional immune cells in immune deficient patients or in bone marrow transplant patients with delayed T cell regeneration. We propose to achieve these goals in the following 2 aims: In Aim 1, we will characterize in detail the long-term, multilineage engraftment potential of the definitive hPSC-derived progenitors. In Aim 2, we will evaluate the engraftment potential of T cell progenitors generated from the hPSC-derived definitive CD34+ progenitors. The findings from these studies have the potential to dramatically impact bone marrow transplantation therapy as they will provide the information necessary for designing stem/progenitor cell grafts that will rapidly restore critical immune functions in transplant patients together with long-term hematopoietic engraftment.
1 avril 2022
31 mars 2024
2022
Martin Levesque (P)
Université Laval
Subventions de soutien aux projects à fort impact
Levesque
Chercheur principal
Martin Levesque, Samer Hussein
183 000
Repairing the dopaminergic circuits in Parkinson disease using synucleinopathy resistant neurones grafting
Parkinson's disease (PD) is a chronic and devastating neurodegenerative disease. It is characterized by the accumulation of intraneuronal Lewy bodies, containing misfolded fibrillar alpha-synuclein (aSyn), and the extensive loss of dopaminergic (DA) neurons in the substantia nigra. Cell replacement therapy aims to restore function in the body by replacing lost, or dysfunctional cells by healthy ones. This regenerative strategy was initially trialed using fetal brain tissue. Clinical studies using grafts of fetal ventral midbrain containing DA neurons, showed that the cells can restore DA neurotransmission and provide functional benefits that are sustained over many years. However, cells obtained from human fetuses are not sufficient to use as a widespread treatment and carry several ethical, and logistical issues. The search for other reliable sources of DA neurons has turned toward the development of methods to generate transplantable cells from renewable sources, such as iPSCs. Although recent progress facilitates cell replacement therapy for PD, there are still hurdles to overcome. One major challenge is the survival of the grafted neurons in a brain environment containing toxic protein aggregates. Analysis of post-mortem brains from PD patients revealed that the grafted neurons acquire a-syn pathology, thus limiting their efficacy and survival, especially in the long term. Our main objective is to develop strategies to promote survival of transplanted DA neurons to efficiently restore the DA deficiencies. Our aims are designed to propose a solution to an important barrier of the effectiveness of cell transplantation i.e. enhance survival of DA neuron engraftment in the pathological brain. To achieve this goal, we have 2 specific objectives. In Aim 1 we will try to enhance survival of transplanted DA neurons by stimulating clearance of protein aggregates. In Aim 2 we will develop a neuroprotective approach for transplanted DA neurons by preventing a-syn pathology spreading. The work will be carried out using a synergistic combination of cultured iPSC-derived DA neurons, brain organoids and a validated PD mouse model. We propose a solution to an important barrier of the cell transplantation therapy for PD, i.e., stimulate survival of these neurons in the pathological brain.
1 avril 2022
31 mars 2024
2022
Samer Hussein (C)
Université Laval
Subventions de soutien aux projects à fort impact
Levesque
Cochercheur
Martin Levesque, Samer Hussein
67 000
Repairing the dopaminergic circuits in Parkinson disease using synucleinopathy resistant neurones grafting
Parkinson's disease (PD) is a chronic and devastating neurodegenerative disease. It is characterized by the accumulation of intraneuronal Lewy bodies, containing misfolded fibrillar alpha-synuclein (aSyn), and the extensive loss of dopaminergic (DA) neurons in the substantia nigra. Cell replacement therapy aims to restore function in the body by replacing lost, or dysfunctional cells by healthy ones. This regenerative strategy was initially trialed using fetal brain tissue. Clinical studies using grafts of fetal ventral midbrain containing DA neurons, showed that the cells can restore DA neurotransmission and provide functional benefits that are sustained over many years. However, cells obtained from human fetuses are not sufficient to use as a widespread treatment and carry several ethical, and logistical issues. The search for other reliable sources of DA neurons has turned toward the development of methods to generate transplantable cells from renewable sources, such as iPSCs. Although recent progress facilitates cell replacement therapy for PD, there are still hurdles to overcome. One major challenge is the survival of the grafted neurons in a brain environment containing toxic protein aggregates. Analysis of post-mortem brains from PD patients revealed that the grafted neurons acquire a-syn pathology, thus limiting their efficacy and survival, especially in the long term. Our main objective is to develop strategies to promote survival of transplanted DA neurons to efficiently restore the DA deficiencies. Our aims are designed to propose a solution to an important barrier of the effectiveness of cell transplantation i.e. enhance survival of DA neuron engraftment in the pathological brain. To achieve this goal, we have 2 specific objectives. In Aim 1 we will try to enhance survival of transplanted DA neurons by stimulating clearance of protein aggregates. In Aim 2 we will develop a neuroprotective approach for transplanted DA neurons by preventing a-syn pathology spreading. The work will be carried out using a synergistic combination of cultured iPSC-derived DA neurons, brain organoids and a validated PD mouse model. We propose a solution to an important barrier of the cell transplantation therapy for PD, i.e., stimulate survival of these neurons in the pathological brain.
1 avril 2022
31 mars 2024
2022
Milica Radisic (P)
University Health Network
Subventions de soutien aux projects à fort impact
Radisic
Chercheur principal
Milica Radisic, Gordon Keller, Michael Laflamme, Slava Epelman
145 000
Stem cell derived resident cardiac macrophages in designer polymers for cardiac repair and regeneration
Resident cardiac macrophages orchestrate healing, they are critically required for regeneration and they have the potential to completely transform cardiac cell therapy by enhancing cardiomyocyte maturation, integration and angiogenesis upon delivery to the ischemic heart. Yet, resident cardiac macrophages cannot currently be obtained due to the following limitations: 1) We do not fully understand their transcriptional signature, so we cannot identify them correctly; 2) Embryonic macrophages can be obtained by directed differentiation of hESC and iPSC from cells similar to yolk sac hematopoietic progenitors. For these primitive macrophages to become resident cardiac macrophages, they need to spend some time in the cardiac environment. Current protocols do not provide for this opportunity; and 3) Embryonic derived macrophages require other cells not just for programming of their identity, but also for their survival, a concept known as a cell circuit. We do not fully understand how to establish and maintain this cell circuit. We will overcome the noted limitations to create improved cardiac cell therapy through the following Specific Aims: Aim 1: We will study published human transcriptomic data and samples of neonatal and adult human hearts from surgeries to define the transcriptional profiles of resident cardiac macrophages. Using heart-on-a-chip, we will program a resident cardiac macrophage fate in hESC and iPSC derived embryonic macrophages. This will enable us to study cell circuits, i.e. interactions between cardiomyocytes, cardiac fibroblasts and macrophages that lead to the development of a resident macrophage phenotype. It will also enable us to study the effects of resident macrophages on cardiomyocyte maturation and contractile force, Ca2+ transients and action potentials. Aim 2: We will engineer microtissues composed of cardiac resident macrophages, fibroblasts and cardiomyocytes capable of re-establishing a functional cell circuit upon injection into the infarcted myocardium. We will inject these microtissues into the infarcted heart of a nude rat using new polymers based on itaconic acid, a powerhouse of the innate immunity, that is known to promote a pro-healing macrophage response in vivo and attenuate inflammation. This approach will enable grafting and integration of the injected tissues to re-muscularize the injured heart
1 avril 2022
31 mars 2024
2022
Gordon Keller (C)
University Health Network
Subventions de soutien aux projects à fort impact
Radisic
Cochercheur
Milica Radisic, Gordon Keller, Michael Laflamme, Slava Epelman
30 000
Stem cell derived resident cardiac macrophages in designer polymers for cardiac repair and regeneration
Resident cardiac macrophages orchestrate healing, they are critically required for regeneration and they have the potential to completely transform cardiac cell therapy by enhancing cardiomyocyte maturation, integration and angiogenesis upon delivery to the ischemic heart. Yet, resident cardiac macrophages cannot currently be obtained due to the following limitations: 1) We do not fully understand their transcriptional signature, so we cannot identify them correctly; 2) Embryonic macrophages can be obtained by directed differentiation of hESC and iPSC from cells similar to yolk sac hematopoietic progenitors. For these primitive macrophages to become resident cardiac macrophages, they need to spend some time in the cardiac environment. Current protocols do not provide for this opportunity; and 3) Embryonic derived macrophages require other cells not just for programming of their identity, but also for their survival, a concept known as a cell circuit. We do not fully understand how to establish and maintain this cell circuit. We will overcome the noted limitations to create improved cardiac cell therapy through the following Specific Aims: Aim 1: We will study published human transcriptomic data and samples of neonatal and adult human hearts from surgeries to define the transcriptional profiles of resident cardiac macrophages. Using heart-on-a-chip, we will program a resident cardiac macrophage fate in hESC and iPSC derived embryonic macrophages. This will enable us to study cell circuits, i.e. interactions between cardiomyocytes, cardiac fibroblasts and macrophages that lead to the development of a resident macrophage phenotype. It will also enable us to study the effects of resident macrophages on cardiomyocyte maturation and contractile force, Ca2+ transients and action potentials. Aim 2: We will engineer microtissues composed of cardiac resident macrophages, fibroblasts and cardiomyocytes capable of re-establishing a functional cell circuit upon injection into the infarcted myocardium. We will inject these microtissues into the infarcted heart of a nude rat using new polymers based on itaconic acid, a powerhouse of the innate immunity, that is known to promote a pro-healing macrophage response in vivo and attenuate inflammation. This approach will enable grafting and integration of the injected tissues to re-muscularize the injured heart
1 avril 2022
31 mars 2024
2022
Michael Laflamme (C)
University Health Network
Subventions de soutien aux projects à fort impact
Radisic
Cochercheur
Milica Radisic, Gordon Keller, Michael Laflamme, Slava Epelman
10 000
Stem cell derived resident cardiac macrophages in designer polymers for cardiac repair and regeneration
Resident cardiac macrophages orchestrate healing, they are critically required for regeneration and they have the potential to completely transform cardiac cell therapy by enhancing cardiomyocyte maturation, integration and angiogenesis upon delivery to the ischemic heart. Yet, resident cardiac macrophages cannot currently be obtained due to the following limitations: 1) We do not fully understand their transcriptional signature, so we cannot identify them correctly; 2) Embryonic macrophages can be obtained by directed differentiation of hESC and iPSC from cells similar to yolk sac hematopoietic progenitors. For these primitive macrophages to become resident cardiac macrophages, they need to spend some time in the cardiac environment. Current protocols do not provide for this opportunity; and 3) Embryonic derived macrophages require other cells not just for programming of their identity, but also for their survival, a concept known as a cell circuit. We do not fully understand how to establish and maintain this cell circuit. We will overcome the noted limitations to create improved cardiac cell therapy through the following Specific Aims: Aim 1: We will study published human transcriptomic data and samples of neonatal and adult human hearts from surgeries to define the transcriptional profiles of resident cardiac macrophages. Using heart-on-a-chip, we will program a resident cardiac macrophage fate in hESC and iPSC derived embryonic macrophages. This will enable us to study cell circuits, i.e. interactions between cardiomyocytes, cardiac fibroblasts and macrophages that lead to the development of a resident macrophage phenotype. It will also enable us to study the effects of resident macrophages on cardiomyocyte maturation and contractile force, Ca2+ transients and action potentials. Aim 2: We will engineer microtissues composed of cardiac resident macrophages, fibroblasts and cardiomyocytes capable of re-establishing a functional cell circuit upon injection into the infarcted myocardium. We will inject these microtissues into the infarcted heart of a nude rat using new polymers based on itaconic acid, a powerhouse of the innate immunity, that is known to promote a pro-healing macrophage response in vivo and attenuate inflammation. This approach will enable grafting and integration of the injected tissues to re-muscularize the injured heart
1 avril 2022
31 mars 2024
2022
Slava Epelman (C)
University Health Network
Subventions de soutien aux projects à fort impact
Radisic
Cochercheur
Milica Radisic, Gordon Keller, Michael Laflamme, Slava Epelman
65 000
Stem cell derived resident cardiac macrophages in designer polymers for cardiac repair and regeneration
Resident cardiac macrophages orchestrate healing, they are critically required for regeneration and they have the potential to completely transform cardiac cell therapy by enhancing cardiomyocyte maturation, integration and angiogenesis upon delivery to the ischemic heart. Yet, resident cardiac macrophages cannot currently be obtained due to the following limitations: 1) We do not fully understand their transcriptional signature, so we cannot identify them correctly; 2) Embryonic macrophages can be obtained by directed differentiation of hESC and iPSC from cells similar to yolk sac hematopoietic progenitors. For these primitive macrophages to become resident cardiac macrophages, they need to spend some time in the cardiac environment. Current protocols do not provide for this opportunity; and 3) Embryonic derived macrophages require other cells not just for programming of their identity, but also for their survival, a concept known as a cell circuit. We do not fully understand how to establish and maintain this cell circuit. We will overcome the noted limitations to create improved cardiac cell therapy through the following Specific Aims: Aim 1: We will study published human transcriptomic data and samples of neonatal and adult human hearts from surgeries to define the transcriptional profiles of resident cardiac macrophages. Using heart-on-a-chip, we will program a resident cardiac macrophage fate in hESC and iPSC derived embryonic macrophages. This will enable us to study cell circuits, i.e. interactions between cardiomyocytes, cardiac fibroblasts and macrophages that lead to the development of a resident macrophage phenotype. It will also enable us to study the effects of resident macrophages on cardiomyocyte maturation and contractile force, Ca2+ transients and action potentials. Aim 2: We will engineer microtissues composed of cardiac resident macrophages, fibroblasts and cardiomyocytes capable of re-establishing a functional cell circuit upon injection into the infarcted myocardium. We will inject these microtissues into the infarcted heart of a nude rat using new polymers based on itaconic acid, a powerhouse of the innate immunity, that is known to promote a pro-healing macrophage response in vivo and attenuate inflammation. This approach will enable grafting and integration of the injected tissues to re-muscularize the injured heart
1 avril 2022
31 mars 2024
2022
Lucie Germain (P)
Université Laval
Subventions de soutien aux projects à fort impact
Germain
Chercheur principal
Lucie Germain, Bartha Knoppers, Elena Pope, Manuel Caruso, Véronique Moulin
223 272
Combining tissue-engineered skin with ex vivo gene therapy correction to develop a treatment for epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease which affects the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for RDEB. The only option is to bandage and care for the recurrent wounds on a daily basis. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction labs in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a treatment for RDEB using the same stem cell culture technology. The objective of this proposal is to complete the necessary steps for the clinical translation of our new therapeutic approach which combines gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce SASS from autologous RDEB cells corrected by in vitro gene therapy beforehand. This proposal AIMS to complete pre-clinical testing for this gene-modified epidermolysis bullosa-self-assembled skin substitute (GMEB-SASS), finalize the necessary documentation for regulatory approval, and initiate a clinical trial to evaluate the treatment’s safety and efficacy. DELIVERABLES: #1 Preclinical testing in vitro and in vivo of GMEB-SASS produced with cGMP COL7A1 retroviral particles; #2 Finalize the documentation for regulatory approval; #3a Submission of a Clinical Trial Application to Health Canada; and #3b Initiate an early phase clinical trial for the treatment of RDEB with autologous GMEB-SASS. Our interdisciplinary team comprises two fundamental investigators (L Germain, an expert in stem cells and tissue engineering; M Caruso, a gene therapy specialist), an expert in socio-ethical and legal issues (BM Knoppers), a pathologist (G St-Jean), a pediatric dermatologist who is the medical director of the largest Canadian EB clinic (E Pope). Our infrastructure, expertise, and knowledge will ensure the success of this project. Ultimately, our goal is to develop a definitive treatment for RDEB. RDEB patients suffer from recurrent wounds, which impacts their quality of life and those of their families. The cost of specialized bandages for their wounds can exceed 100,000$/year. Therefore, this new treatment, if proven successful, could change the lives of Canadian RDEB patients by improving skin stability and preventing recurring wounds.
1 avril 2022
31 mars 2024
2022
Bartha Knoppers (C)
Université McGill
Subventions de soutien aux projects à fort impact
Germain
Cochercheur
Lucie Germain, Bartha Knoppers, Elena Pope, Manuel Caruso, Véronique Moulin
10 000
Combining tissue-engineered skin with ex vivo gene therapy correction to develop a treatment for epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease which affects the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for RDEB. The only option is to bandage and care for the recurrent wounds on a daily basis. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction labs in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a treatment for RDEB using the same stem cell culture technology. The objective of this proposal is to complete the necessary steps for the clinical translation of our new therapeutic approach which combines gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce SASS from autologous RDEB cells corrected by in vitro gene therapy beforehand. This proposal AIMS to complete pre-clinical testing for this gene-modified epidermolysis bullosa-self-assembled skin substitute (GMEB-SASS), finalize the necessary documentation for regulatory approval, and initiate a clinical trial to evaluate the treatment’s safety and efficacy. DELIVERABLES: #1 Preclinical testing in vitro and in vivo of GMEB-SASS produced with cGMP COL7A1 retroviral particles; #2 Finalize the documentation for regulatory approval; #3a Submission of a Clinical Trial Application to Health Canada; and #3b Initiate an early phase clinical trial for the treatment of RDEB with autologous GMEB-SASS. Our interdisciplinary team comprises two fundamental investigators (L Germain, an expert in stem cells and tissue engineering; M Caruso, a gene therapy specialist), an expert in socio-ethical and legal issues (BM Knoppers), a pathologist (G St-Jean), a pediatric dermatologist who is the medical director of the largest Canadian EB clinic (E Pope). Our infrastructure, expertise, and knowledge will ensure the success of this project. Ultimately, our goal is to develop a definitive treatment for RDEB. RDEB patients suffer from recurrent wounds, which impacts their quality of life and those of their families. The cost of specialized bandages for their wounds can exceed 100,000$/year. Therefore, this new treatment, if proven successful, could change the lives of Canadian RDEB patients by improving skin stability and preventing recurring wounds.
1 avril 2022
31 mars 2024
2022
Elena Pope (C)
Hospital for Sick Children
Subventions de soutien aux projects à fort impact
Germain
Cochercheur
Lucie Germain, Bartha Knoppers, Elena Pope, Manuel Caruso, Véronique Moulin
5 000
Combining tissue-engineered skin with ex vivo gene therapy correction to develop a treatment for epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease which affects the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for RDEB. The only option is to bandage and care for the recurrent wounds on a daily basis. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction labs in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a treatment for RDEB using the same stem cell culture technology. The objective of this proposal is to complete the necessary steps for the clinical translation of our new therapeutic approach which combines gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce SASS from autologous RDEB cells corrected by in vitro gene therapy beforehand. This proposal AIMS to complete pre-clinical testing for this gene-modified epidermolysis bullosa-self-assembled skin substitute (GMEB-SASS), finalize the necessary documentation for regulatory approval, and initiate a clinical trial to evaluate the treatment’s safety and efficacy. DELIVERABLES: #1 Preclinical testing in vitro and in vivo of GMEB-SASS produced with cGMP COL7A1 retroviral particles; #2 Finalize the documentation for regulatory approval; #3a Submission of a Clinical Trial Application to Health Canada; and #3b Initiate an early phase clinical trial for the treatment of RDEB with autologous GMEB-SASS. Our interdisciplinary team comprises two fundamental investigators (L Germain, an expert in stem cells and tissue engineering; M Caruso, a gene therapy specialist), an expert in socio-ethical and legal issues (BM Knoppers), a pathologist (G St-Jean), a pediatric dermatologist who is the medical director of the largest Canadian EB clinic (E Pope). Our infrastructure, expertise, and knowledge will ensure the success of this project. Ultimately, our goal is to develop a definitive treatment for RDEB. RDEB patients suffer from recurrent wounds, which impacts their quality of life and those of their families. The cost of specialized bandages for their wounds can exceed 100,000$/year. Therefore, this new treatment, if proven successful, could change the lives of Canadian RDEB patients by improving skin stability and preventing recurring wounds.
1 avril 2022
31 mars 2024
2022
Manuel Caruso (C)
Université Laval
Subventions de soutien aux projects à fort impact
Germain
Cochercheur
Lucie Germain, Bartha Knoppers, Elena Pope, Manuel Caruso, Véronique Moulin
7 200
Combining tissue-engineered skin with ex vivo gene therapy correction to develop a treatment for epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease which affects the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for RDEB. The only option is to bandage and care for the recurrent wounds on a daily basis. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction labs in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a treatment for RDEB using the same stem cell culture technology. The objective of this proposal is to complete the necessary steps for the clinical translation of our new therapeutic approach which combines gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce SASS from autologous RDEB cells corrected by in vitro gene therapy beforehand. This proposal AIMS to complete pre-clinical testing for this gene-modified epidermolysis bullosa-self-assembled skin substitute (GMEB-SASS), finalize the necessary documentation for regulatory approval, and initiate a clinical trial to evaluate the treatment’s safety and efficacy. DELIVERABLES: #1 Preclinical testing in vitro and in vivo of GMEB-SASS produced with cGMP COL7A1 retroviral particles; #2 Finalize the documentation for regulatory approval; #3a Submission of a Clinical Trial Application to Health Canada; and #3b Initiate an early phase clinical trial for the treatment of RDEB with autologous GMEB-SASS. Our interdisciplinary team comprises two fundamental investigators (L Germain, an expert in stem cells and tissue engineering; M Caruso, a gene therapy specialist), an expert in socio-ethical and legal issues (BM Knoppers), a pathologist (G St-Jean), a pediatric dermatologist who is the medical director of the largest Canadian EB clinic (E Pope). Our infrastructure, expertise, and knowledge will ensure the success of this project. Ultimately, our goal is to develop a definitive treatment for RDEB. RDEB patients suffer from recurrent wounds, which impacts their quality of life and those of their families. The cost of specialized bandages for their wounds can exceed 100,000$/year. Therefore, this new treatment, if proven successful, could change the lives of Canadian RDEB patients by improving skin stability and preventing recurring wounds.
1 avril 2022
31 mars 2024
2022
Véronique Moulin (C)
Université Laval
Subventions de soutien aux projects à fort impact
Germain
Cochercheur
Lucie Germain, Bartha Knoppers, Elena Pope, Manuel Caruso, Véronique Moulin
4 528
Combining tissue-engineered skin with ex vivo gene therapy correction to develop a treatment for epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease which affects the skin and mucosa. RDEB patients have very fragile skin due to a mutation in the collagen 7 gene. At present, there is no cure for RDEB. The only option is to bandage and care for the recurrent wounds on a daily basis. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction labs in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a treatment for RDEB using the same stem cell culture technology. The objective of this proposal is to complete the necessary steps for the clinical translation of our new therapeutic approach which combines gene therapy and tissue engineering. In order to develop a treatment for RDEB, our strategy is to produce SASS from autologous RDEB cells corrected by in vitro gene therapy beforehand. This proposal AIMS to complete pre-clinical testing for this gene-modified epidermolysis bullosa-self-assembled skin substitute (GMEB-SASS), finalize the necessary documentation for regulatory approval, and initiate a clinical trial to evaluate the treatment’s safety and efficacy. DELIVERABLES: #1 Preclinical testing in vitro and in vivo of GMEB-SASS produced with cGMP COL7A1 retroviral particles; #2 Finalize the documentation for regulatory approval; #3a Submission of a Clinical Trial Application to Health Canada; and #3b Initiate an early phase clinical trial for the treatment of RDEB with autologous GMEB-SASS. Our interdisciplinary team comprises two fundamental investigators (L Germain, an expert in stem cells and tissue engineering; M Caruso, a gene therapy specialist), an expert in socio-ethical and legal issues (BM Knoppers), a pathologist (G St-Jean), a pediatric dermatologist who is the medical director of the largest Canadian EB clinic (E Pope). Our infrastructure, expertise, and knowledge will ensure the success of this project. Ultimately, our goal is to develop a definitive treatment for RDEB. RDEB patients suffer from recurrent wounds, which impacts their quality of life and those of their families. The cost of specialized bandages for their wounds can exceed 100,000$/year. Therefore, this new treatment, if proven successful, could change the lives of Canadian RDEB patients by improving skin stability and preventing recurring wounds.
1 avril 2022
31 mars 2024
2022
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien aux projects à fort impact
Thébaud
Chercheur principal
Bernard Thébaud
249 976
Ironman – Improved Respiratory Outcome of Newborns with Modified Angiogenic Nanovesicles
The objective is to develop a novel vascular progenitor cell-derived therapy for neonatal pulmonary hypertension (PH). Extreme prematurity is the leading cause of death in children below 5 years. Chronic lung disease is the most frequent cause of death or life-long morbidity in these children. PH is a major factor limiting survival. The reduction of the pulmonary vascular bed in these patients renders current therapies – aiming at vasodilatation only – obsolete. Thus, promoting lung vascular growth may improve PH. We identified lung resident endothelial colony forming cells (ECFC) – a subset of vascular progenitor cells with self-renewal and de novo angiogenesis capacity – in the developing lung. We showed that cord blood-derived ECFC promote lung vascular growth and repair in experimental neonatal lung injury. Our new findings indicate that this therapeutic benefit is mediated via small extra-cellular vesicles (sEV). We have capitalized on new technology to produce high quality sEV at clinical scale using Tangential Flow Filtration (TFF). Furthermore, through our partner Vascugen, we have access to a unique and novel induced pluripotent stem cell-derived vascular progenitor cell (VSC100) with ECFC properties. This provides the advantage of producing consistent, high quality cells in clinically relevant numbers. Combined, these technologies represent a two-fold innovation and open the exciting prospect for allogeneic, off-the-shelf cell-based therapy for PH. We will provide proof-of-concept for a novel vascular progenitor cell-derived therapy for neonatal PH through these deliverables: 1- Establish therapeutic potential of TFF-generated VSC100-sEV 2- Establish optimal dose and route of administration of VSC100-sEV 3- Establish safety of VSC-sEV 4- Identify potential therapeutic miRNA within VSC100-sEV Research excellence is provided by the novelty; importance; a world-class team composed of world-leaders in lung, vascular progenitor cell, and EV biology; and a track-record of successful clinical translation. As such, our VSC100-derived sEV has high potential to be translated into Health, Economic (new IP, spin-off, partnerships, tackling the manufacturing dearth in Canada, as witnessed by the pandemic) and Social benefits (children are neglected in R&D and Canada ranks in the bottom third in children well-being, unicef.ca; job creation).
1 avril 2022
31 mars 2024
2022
Lauren Flynn (P)
University of Western Ontario
Subventions de soutien aux projects à fort impact
Flynn
Chercheur principal
Lauren Flynn, John Ronald
230 000
Delivery of adipose-derived stromal cells within novel cell-assembled bioscaffolds for the treatment of chronic wounds
Chronic or non-healing skin wounds represent a significant and growing clinical problem that affects the health and quality of life of many Canadians. The cost of treating these wounds places a substantial burden on healthcare systems around the globe. Unfortunately, despite the wide variety of dressings available on the market, efficacy is often limited, and treatment times are long and costly. For patients who develop serious infections or repeatedly fail to respond, amputation of the affected limb is often necessary. This project will investigate a promising cell therapy platform that harnesses the synergistic pro-regenerative capacities of adipose-derived stromal cells (ASCs) and decellularized adipose tissue (DAT) scaffolds derived from human fat discarded as surgical waste as a novel strategy to overcome the pro-inflammatory microenvironment within the chronic wound bed, stimulate angiogenesis, and promote wound closure. More specifically, the Flynn lab recently developed patented “cell-assembled” DAT scaffolds that contain a high density and even distribution of ASCs, which have shown promise for stimulating vascular regeneration. The current proposal will transition our research from technological development to biological validation of our platform as a strategy to promote cutaneous wound healing for the first time. We hypothesize that our unique cell therapy platform will establish a pro-regenerative milieu within the wound bed that will augment healing. In-depth pre-clinical testing in the db/db mouse impaired wound healing model will verify the effects on wound closure and help to elucidate the mechanisms of ASC-mediated regeneration. In addition, proof-of-concept studies in a porcine wound model will generate key data required to advance towards clinical trials. Importantly, we have integrated advanced imaging technologies into our approach in both models that will allow us to longitudinally track the viable ASCs delivered to the wounds and probe angiogenesis within the wound beds. We have assembled a strong interdisciplinary team of experts in cell therapies, wound healing, pre-clinical models, and imaging, to generate the essential data needed to secure a strong partnership with an experienced company in the advanced wound care sector willing to license our intellectual property and invest in its further development and commercialization.
1 avril 2022
31 mars 2024
2022
John Ronald (C)
University of Western Ontario
Subventions de soutien aux projects à fort impact
Flynn
Cochercheur
Lauren Flynn, John Ronald
20 000
Delivery of adipose-derived stromal cells within novel cell-assembled bioscaffolds for the treatment of chronic wounds
Chronic or non-healing skin wounds represent a significant and growing clinical problem that affects the health and quality of life of many Canadians. The cost of treating these wounds places a substantial burden on healthcare systems around the globe. Unfortunately, despite the wide variety of dressings available on the market, efficacy is often limited, and treatment times are long and costly. For patients who develop serious infections or repeatedly fail to respond, amputation of the affected limb is often necessary. This project will investigate a promising cell therapy platform that harnesses the synergistic pro-regenerative capacities of adipose-derived stromal cells (ASCs) and decellularized adipose tissue (DAT) scaffolds derived from human fat discarded as surgical waste as a novel strategy to overcome the pro-inflammatory microenvironment within the chronic wound bed, stimulate angiogenesis, and promote wound closure. More specifically, the Flynn lab recently developed patented “cell-assembled” DAT scaffolds that contain a high density and even distribution of ASCs, which have shown promise for stimulating vascular regeneration. The current proposal will transition our research from technological development to biological validation of our platform as a strategy to promote cutaneous wound healing for the first time. We hypothesize that our unique cell therapy platform will establish a pro-regenerative milieu within the wound bed that will augment healing. In-depth pre-clinical testing in the db/db mouse impaired wound healing model will verify the effects on wound closure and help to elucidate the mechanisms of ASC-mediated regeneration. In addition, proof-of-concept studies in a porcine wound model will generate key data required to advance towards clinical trials. Importantly, we have integrated advanced imaging technologies into our approach in both models that will allow us to longitudinally track the viable ASCs delivered to the wounds and probe angiogenesis within the wound beds. We have assembled a strong interdisciplinary team of experts in cell therapies, wound healing, pre-clinical models, and imaging, to generate the essential data needed to secure a strong partnership with an experienced company in the advanced wound care sector willing to license our intellectual property and invest in its further development and commercialization.
1 avril 2022
31 mars 2024
2022
Molly Shoichet (P)
University of Toronto
Subventions de soutien aux projects à fort impact
Shoichet
Chercheur principal
Molly Shoichet, Andras Nagy, Cindi Morshead
110 000
Regenerating the Stroke Injured Brain by Modulating the Glial Scar and Enhancing Neuroplasticity
We propose to overcome the devastation of stroke by regenerating the brain. We will modulate the glial scar and enhance neuroplasticity with local delivery of therapeutics and cells to regenerate the brain and recover function. After traumatic injury in the central nervous system (CNS), a glial scar forms, comprised of chondroitin sulfate proteoglycans. The glial scar both limits the spread of tissue degeneration and inhibits neural regeneration. We propose that chondrotinase ABC (ChASE) will overcome this barrier and that neural stem cells will promote tissue regeneration. ChASE is a potent, yet fragile enzyme, that degrades the glial scar formed after traumatic injury in the CNS and provides neuroprotection. We propose to study ChASE in stroke; however, because the enzyme degrades easily, it requires repeated injection and/or delivery by viral vectors. As neither of these solutions are optimal, we made 2 key inventions that we patented for commercialization: (1) we re-engineered ChASE to have 37-point mutations (ChASE37); and (2) we designed an affinity release system for its controlled delivery, ChASE37-AR. Neural progenitor cells promote tissue and functional repair after transplantation in the acute or subacute stroke-injured brain. We have shown that cortical neuroepithelial cells (cNEPs) are advantageous for functional recovery. By co-delivery with ChASE37-AR, which will modulate the microenvironment, we hypothesize functional integration and survival of cNEPs, leading to brain regeneration and behavioural repair. We propose to examine the effects of ChASE37-AR and cloaked cNEPs in promoting recovery in pre-clinical animal models of subacute stroke: 1. Co-deliver cNEPs and ChASE37-AR to the stroke injured brain to investigate tissue regeneration and functional outcomes relative to controls of each variable alone. 2. Understand how the delivery ChASE37-AR impacts the glial scar and neuroplasticity after injection into the stroke-injured rodent brain. To achieve success, we have assembled a world-renowned team of experts in bioengineering (Shoichet, UofT), neural stem cell biology (Morshead, UofT; Nagy, Lunenfeld), and neurosurgery and neurology (Lipsman and Swartz, Sunnybrook). In addition to research excellence, we have translational experience and will leverage funding from partners.
1 avril 2022
31 mars 2024
2022
Andras Nagy (C)
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Subventions de soutien aux projects à fort impact
Shoichet
Cochercheur
Molly Shoichet, Andras Nagy, Cindi Morshead
30 000
Regenerating the Stroke Injured Brain by Modulating the Glial Scar and Enhancing Neuroplasticity
We propose to overcome the devastation of stroke by regenerating the brain. We will modulate the glial scar and enhance neuroplasticity with local delivery of therapeutics and cells to regenerate the brain and recover function. After traumatic injury in the central nervous system (CNS), a glial scar forms, comprised of chondroitin sulfate proteoglycans. The glial scar both limits the spread of tissue degeneration and inhibits neural regeneration. We propose that chondrotinase ABC (ChASE) will overcome this barrier and that neural stem cells will promote tissue regeneration. ChASE is a potent, yet fragile enzyme, that degrades the glial scar formed after traumatic injury in the CNS and provides neuroprotection. We propose to study ChASE in stroke; however, because the enzyme degrades easily, it requires repeated injection and/or delivery by viral vectors. As neither of these solutions are optimal, we made 2 key inventions that we patented for commercialization: (1) we re-engineered ChASE to have 37-point mutations (ChASE37); and (2) we designed an affinity release system for its controlled delivery, ChASE37-AR. Neural progenitor cells promote tissue and functional repair after transplantation in the acute or subacute stroke-injured brain. We have shown that cortical neuroepithelial cells (cNEPs) are advantageous for functional recovery. By co-delivery with ChASE37-AR, which will modulate the microenvironment, we hypothesize functional integration and survival of cNEPs, leading to brain regeneration and behavioural repair. We propose to examine the effects of ChASE37-AR and cloaked cNEPs in promoting recovery in pre-clinical animal models of subacute stroke: 1. Co-deliver cNEPs and ChASE37-AR to the stroke injured brain to investigate tissue regeneration and functional outcomes relative to controls of each variable alone. 2. Understand how the delivery ChASE37-AR impacts the glial scar and neuroplasticity after injection into the stroke-injured rodent brain. To achieve success, we have assembled a world-renowned team of experts in bioengineering (Shoichet, UofT), neural stem cell biology (Morshead, UofT; Nagy, Lunenfeld), and neurosurgery and neurology (Lipsman and Swartz, Sunnybrook). In addition to research excellence, we have translational experience and will leverage funding from partners.
1 avril 2022
31 mars 2024
2022
Cindi Morshead (C)
University of Toronto
Subventions de soutien aux projects à fort impact
Shoichet
Cochercheur
Molly Shoichet, Andras Nagy, Cindi Morshead
110 000
Regenerating the Stroke Injured Brain by Modulating the Glial Scar and Enhancing Neuroplasticity
We propose to overcome the devastation of stroke by regenerating the brain. We will modulate the glial scar and enhance neuroplasticity with local delivery of therapeutics and cells to regenerate the brain and recover function. After traumatic injury in the central nervous system (CNS), a glial scar forms, comprised of chondroitin sulfate proteoglycans. The glial scar both limits the spread of tissue degeneration and inhibits neural regeneration. We propose that chondrotinase ABC (ChASE) will overcome this barrier and that neural stem cells will promote tissue regeneration. ChASE is a potent, yet fragile enzyme, that degrades the glial scar formed after traumatic injury in the CNS and provides neuroprotection. We propose to study ChASE in stroke; however, because the enzyme degrades easily, it requires repeated injection and/or delivery by viral vectors. As neither of these solutions are optimal, we made 2 key inventions that we patented for commercialization: (1) we re-engineered ChASE to have 37-point mutations (ChASE37); and (2) we designed an affinity release system for its controlled delivery, ChASE37-AR. Neural progenitor cells promote tissue and functional repair after transplantation in the acute or subacute stroke-injured brain. We have shown that cortical neuroepithelial cells (cNEPs) are advantageous for functional recovery. By co-delivery with ChASE37-AR, which will modulate the microenvironment, we hypothesize functional integration and survival of cNEPs, leading to brain regeneration and behavioural repair. We propose to examine the effects of ChASE37-AR and cloaked cNEPs in promoting recovery in pre-clinical animal models of subacute stroke: 1. Co-deliver cNEPs and ChASE37-AR to the stroke injured brain to investigate tissue regeneration and functional outcomes relative to controls of each variable alone. 2. Understand how the delivery ChASE37-AR impacts the glial scar and neuroplasticity after injection into the stroke-injured rodent brain. To achieve success, we have assembled a world-renowned team of experts in bioengineering (Shoichet, UofT), neural stem cell biology (Morshead, UofT; Nagy, Lunenfeld), and neurosurgery and neurology (Lipsman and Swartz, Sunnybrook). In addition to research excellence, we have translational experience and will leverage funding from partners.
1 avril 2022
31 mars 2024
2022
Pamela Hoodless (P)
University of British Columbia
Subventions de soutien aux projects à fort impact
Hoodless
Chercheur principal
Pamela Hoodless
250 000
Pathways of Cell Identity in Human Liver Organoids
Multiples maladies
Liver, Organoids, Human pluripotent stem cells, Signal Transduction, Cell-cell interactions, Lineage Tracing
iver transplants are on the rise. Cell therapy has been successfully used to treat patients with liver failure. However, acquiring sufficient supplies of hepatocytes (the primary functional cell of the liver) is problematic. Recent advances in the differentiation of human pluripotent stem cells (hPSCs) into hepatocytes may provide a potential source of cells for transplants, drug testing and bioartificial liver devices. However, current methods only produce immature hepatocytes. Moreover, the complex and highly organized structure of the adult liver required for normal organ function is not produced. Insight into factors that promote and establish the permissive environment for early hepatic differentiation may inform better methods for hepatic output by allowing functional cell-cell relationships to be established. We are using hPSC-derived organoids to study the formation of liver. Based on a method developed in the laboratory of G. Sullivan (University of Oslo), we are using a simple suspension culture that leverages the ability of hPSCs to self-aggregate on seeding as single cells. Aggregates are stimulated with the addition of small molecules to generate “mini-liver” organoids which recapitulate the complexity of cell types associated with liver. We will use these organoids to probe the relationship of cells in the organoids and to explore communication between cell types through signalling pathways and how they control cell identity and structure. For this proposal, we have two specific aims. Aim 1: Determine the Lineage relationships between hepatic organoid cell types. We will use an evolving bar-code based on a high-content CRISPR cell lineage tracing system to determine the relationships and evolution of cell identity within liver organoids. The bar-codes are read via high-throughput single cell sequencing which captures the expression profiles and the lineage history of each cell. Aim 2: Evaluate the cell diversity and interactions that drive differentiation in human hepatic organoids. We will analyze the single cell expression data to identify cell diversity generated at various stages of for potential pathway interactions between cell types as organoids develop. Comparison with data obtained in mouse embryos will identify common and unique pathways.
1 avril 2022
31 mars 2024
2022
Karun Singh (P)
University Health Network
Subventions de soutien aux projects à fort impact
Singh
Chercheur principal
Karun Singh, Sarah Wootton
235 000
Gene therapy to restore neural connectivity in neurodevelopmental disorders associated with a CNV microdeletion
Genomic copy number variations (CNVs) are structural variations that involve deletions and/or duplications of segments of DNA. They are frequently associated with disease, and represent a major class of risk factors for neurodevelopmental disorders (NDDs). Large recurrent (common) deletions are the most severe, and there are no specific treatments due to a lack of understanding of disease mechanisms. We are studying the common 15q13.3 deletion that is associated with epilepsy, schizophrenia, autism spectrum disorder and developmental delay, occurring in 1 in 2500-5000 individuals. The genomic region affected contains ~10 genes. There are no treatments that reverse or cure the symptoms and impairments experienced by individuals, which cause life-long disabilities. We identified that one of the ten genes (OTUD7A) is likely responsible for mediating the major clinical outcomes associated with this deletion. Specifically, we found that OTUD7A is a driver of dendrite, axonal and neuronal excitability defects in patient iPSC-neurons, which could contribute to cognitive and learning deficits. Moreover, given that reduced gene dosage in the 15q13.3 interval genes a key pathogenic mechanism, approaches to restore gene expression using viral gene therapy would be proof of principle experiments to pave the way for future treatments. We have assembled three experts to use adeno-associated virus (AAV) gene therapy to correct neuronal dysfunction in the 15q13.3 deletion. We will restore the expression of key 15q13.3 deletion gene(s) that are causing abnormalities in neural connectivity. Our is strategy is to initially restore the function of OTUD7A given our preliminary data, which we predict will lead to a recovery of axonal and synaptic connectivity. This will be assessed using a novel 3D brain organoid-based axon connectivity assay we established by fusing organoids, together with tissue clearing and light-sheet microscopy to examine structural axonal connectivity, while electrophysiology will assess function. We will also use bulk and single-cell RNA sequencing to understand the underlying mechanism involved in gene therapy regenerating functional neural connectivity. Together, this project will test gene therapy as a possible regenerative therapy for NDDs caused by microdeletions, and will pave a path forward to restore neuronal connectivity in other NDDs.
1 avril 2022
31 mars 2024
2022
Sarah Wootton (C)
University of Guelph
Subventions de soutien aux projects à fort impact
Singh
Cochercheur
Karun Singh, Sarah Wootton
15 000
Gene therapy to restore neural connectivity in neurodevelopmental disorders associated with a CNV microdeletion
Genomic copy number variations (CNVs) are structural variations that involve deletions and/or duplications of segments of DNA. They are frequently associated with disease, and represent a major class of risk factors for neurodevelopmental disorders (NDDs). Large recurrent (common) deletions are the most severe, and there are no specific treatments due to a lack of understanding of disease mechanisms. We are studying the common 15q13.3 deletion that is associated with epilepsy, schizophrenia, autism spectrum disorder and developmental delay, occurring in 1 in 2500-5000 individuals. The genomic region affected contains ~10 genes. There are no treatments that reverse or cure the symptoms and impairments experienced by individuals, which cause life-long disabilities. We identified that one of the ten genes (OTUD7A) is likely responsible for mediating the major clinical outcomes associated with this deletion. Specifically, we found that OTUD7A is a driver of dendrite, axonal and neuronal excitability defects in patient iPSC-neurons, which could contribute to cognitive and learning deficits. Moreover, given that reduced gene dosage in the 15q13.3 interval genes a key pathogenic mechanism, approaches to restore gene expression using viral gene therapy would be proof of principle experiments to pave the way for future treatments. We have assembled three experts to use adeno-associated virus (AAV) gene therapy to correct neuronal dysfunction in the 15q13.3 deletion. We will restore the expression of key 15q13.3 deletion gene(s) that are causing abnormalities in neural connectivity. Our is strategy is to initially restore the function of OTUD7A given our preliminary data, which we predict will lead to a recovery of axonal and synaptic connectivity. This will be assessed using a novel 3D brain organoid-based axon connectivity assay we established by fusing organoids, together with tissue clearing and light-sheet microscopy to examine structural axonal connectivity, while electrophysiology will assess function. We will also use bulk and single-cell RNA sequencing to understand the underlying mechanism involved in gene therapy regenerating functional neural connectivity. Together, this project will test gene therapy as a possible regenerative therapy for NDDs caused by microdeletions, and will pave a path forward to restore neuronal connectivity in other NDDs.
Cell therapies hold much promise for the treatment and prevention of disease. Minors are frequently the focus of such interventions, meant to prevent or investigate the expression of early onset diseases, and their inclusion as research participants in clinical trials requires unique ethical and legal protections. This project explores ways to facilitate the responsible clinical translation of cell and gene therapies for the benefit of children, by addressing knowledge gaps and developing resources for researchers, clinicians, families, REBs, policymakers and regulators. To achieve this, we will address: • Research trajectories: development of tools to assist in the design and assessment of safety, efficacy, and the balance of risks and potential benefits, when moving to first-in-human clinical trials. • Responsibilities: enhanced conceptual clarity regarding the legal and ethical roles and responsibilities of clinicians / researchers. • Rights of children: analysis of the ambit and implications of the rights and best interests of children and minors, and the capacity to make autonomous decisions regarding their involvement in cellular genomics clinical trials.
Cell therapies hold much promise for the treatment and prevention of disease. Minors are frequently the focus of such interventions, meant to prevent or investigate the expression of early onset diseases, and their inclusion as research participants in clinical trials requires unique ethical and legal protections. This project explores ways to facilitate the responsible clinical translation of cell and gene therapies for the benefit of children, by addressing knowledge gaps and developing resources for researchers, clinicians, families, REBs, policymakers and regulators. To achieve this, we will address: • Research trajectories: development of tools to assist in the design and assessment of safety, efficacy, and the balance of risks and potential benefits, when moving to first-in-human clinical trials. • Responsibilities: enhanced conceptual clarity regarding the legal and ethical roles and responsibilities of clinicians / researchers. • Rights of children: analysis of the ambit and implications of the rights and best interests of children and minors, and the capacity to make autonomous decisions regarding their involvement in cellular genomics clinical trials.
Cell therapies hold much promise for the treatment and prevention of disease. Minors are frequently the focus of such interventions, meant to prevent or investigate the expression of early onset diseases, and their inclusion as research participants in clinical trials requires unique ethical and legal protections. This project explores ways to facilitate the responsible clinical translation of cell and gene therapies for the benefit of children, by addressing knowledge gaps and developing resources for researchers, clinicians, families, REBs, policymakers and regulators. To achieve this, we will address: • Research trajectories: development of tools to assist in the design and assessment of safety, efficacy, and the balance of risks and potential benefits, when moving to first-in-human clinical trials. • Responsibilities: enhanced conceptual clarity regarding the legal and ethical roles and responsibilities of clinicians / researchers. • Rights of children: analysis of the ambit and implications of the rights and best interests of children and minors, and the capacity to make autonomous decisions regarding their involvement in cellular genomics clinical trials.
1 avril 2022
31 janvier 2025
2022
Amy Zarzeczny (P)
University of Regina
Subventions du programme Applications et Société
Zarzeczny
Chercheur principal
Amy Zarzeczny, Timothy Caulfield, Ubaka Ogbogu
250 465
Law, Public Policy and Social License for Next-Generation Regenerative Medicine
QEJS, questions éthiques, juridiques et sociales
Regenerative medicine, law, policy, regulation, governance, public perception, social license
We are at a critical time for clinical translation of regenerative medicine, which offers potential life-changing improvements to treatment options for many conditions. Successful clinical translation will require regulation and governance frameworks (tools, institutions and processes) that support development of safe, effective and globally accessible treatments, and which prevent illegitimate, premature, and unethical translation. It is important these frameworks operate in a context that promotes public trust, inclusive innovation and technology uptake, and global health justice. This context is necessary to maintain regenerative medicine’s social license to operate. The objective of this project is to support development of an inclusive regulatory and governance framework that will strengthen the social license for the clinical translation of regenerative medicine. We will do so by advancing knowledge in three key areas: (1) Design and updating of regulatory systems that support sustainable and equitable innovation and technology translation; (2) Understanding misinformation about regenerative medicine and its relationship with public trust; (3) Strengthening professional regulation as a governance mechanism for clinical applications of regenerative medicine. We will take an innovative approach, adopting a global justice lens for our work. Notable deliverables will include recommendations for policy and regulatory reform, academic publications and presentations, writings for the popular press, high-impact Policy Briefs, and training for Highly Qualified Personnel (HQP). We have assembled a strong and diverse team, many of whom have a history of successful collaboration in stem cell and regenerative medicine research. Our multidisciplinary team brings expertise in law, policy, ethics, stem cell science, regulation, governance, media studies, global health, public engagement and knowledge translation, among other areas, as well as international perspectives (including the US, Australia, Europe, and South Africa). We will leverage key partnerships, including #ScienceUpFirst, EuroGCT and the Centre for the Study of Science and Innovation Policy, to enhance the reach and impact of our work. HQP will have a central role in all aspects of the project, building on the Health Law Institute's successful training model.
1 avril 2022
31 janvier 2025
2022
Timothy Caulfield (C)
University of Alberta
Subventions du programme Applications et Société
Zarzeczny
Cochercheur
Amy Zarzeczny, Timothy Caulfield, Ubaka Ogbogu
265 830
Law, Public Policy and Social License for Next-Generation Regenerative Medicine
QEJS, questions éthiques, juridiques et sociales
Regenerative medicine, law, policy, regulation, governance, public perception, social license
We are at a critical time for clinical translation of regenerative medicine, which offers potential life-changing improvements to treatment options for many conditions. Successful clinical translation will require regulation and governance frameworks (tools, institutions and processes) that support development of safe, effective and globally accessible treatments, and which prevent illegitimate, premature, and unethical translation. It is important these frameworks operate in a context that promotes public trust, inclusive innovation and technology uptake, and global health justice. This context is necessary to maintain regenerative medicine’s social license to operate. The objective of this project is to support development of an inclusive regulatory and governance framework that will strengthen the social license for the clinical translation of regenerative medicine. We will do so by advancing knowledge in three key areas: (1) Design and updating of regulatory systems that support sustainable and equitable innovation and technology translation; (2) Understanding misinformation about regenerative medicine and its relationship with public trust; (3) Strengthening professional regulation as a governance mechanism for clinical applications of regenerative medicine. We will take an innovative approach, adopting a global justice lens for our work. Notable deliverables will include recommendations for policy and regulatory reform, academic publications and presentations, writings for the popular press, high-impact Policy Briefs, and training for Highly Qualified Personnel (HQP). We have assembled a strong and diverse team, many of whom have a history of successful collaboration in stem cell and regenerative medicine research. Our multidisciplinary team brings expertise in law, policy, ethics, stem cell science, regulation, governance, media studies, global health, public engagement and knowledge translation, among other areas, as well as international perspectives (including the US, Australia, Europe, and South Africa). We will leverage key partnerships, including #ScienceUpFirst, EuroGCT and the Centre for the Study of Science and Innovation Policy, to enhance the reach and impact of our work. HQP will have a central role in all aspects of the project, building on the Health Law Institute's successful training model.
1 avril 2022
31 janvier 2025
2022
Ubaka Ogbogu (C)
University of Alberta
Subventions du programme Applications et Société
Zarzeczny
Cochercheur
Amy Zarzeczny, Timothy Caulfield, Ubaka Ogbogu
188 690
Law, Public Policy and Social License for Next-Generation Regenerative Medicine
QEJS, questions éthiques, juridiques et sociales
Regenerative medicine, law, policy, regulation, governance, public perception, social license
We are at a critical time for clinical translation of regenerative medicine, which offers potential life-changing improvements to treatment options for many conditions. Successful clinical translation will require regulation and governance frameworks (tools, institutions and processes) that support development of safe, effective and globally accessible treatments, and which prevent illegitimate, premature, and unethical translation. It is important these frameworks operate in a context that promotes public trust, inclusive innovation and technology uptake, and global health justice. This context is necessary to maintain regenerative medicine’s social license to operate. The objective of this project is to support development of an inclusive regulatory and governance framework that will strengthen the social license for the clinical translation of regenerative medicine. We will do so by advancing knowledge in three key areas: (1) Design and updating of regulatory systems that support sustainable and equitable innovation and technology translation; (2) Understanding misinformation about regenerative medicine and its relationship with public trust; (3) Strengthening professional regulation as a governance mechanism for clinical applications of regenerative medicine. We will take an innovative approach, adopting a global justice lens for our work. Notable deliverables will include recommendations for policy and regulatory reform, academic publications and presentations, writings for the popular press, high-impact Policy Briefs, and training for Highly Qualified Personnel (HQP). We have assembled a strong and diverse team, many of whom have a history of successful collaboration in stem cell and regenerative medicine research. Our multidisciplinary team brings expertise in law, policy, ethics, stem cell science, regulation, governance, media studies, global health, public engagement and knowledge translation, among other areas, as well as international perspectives (including the US, Australia, Europe, and South Africa). We will leverage key partnerships, including #ScienceUpFirst, EuroGCT and the Centre for the Study of Science and Innovation Policy, to enhance the reach and impact of our work. HQP will have a central role in all aspects of the project, building on the Health Law Institute's successful training model.
1 avril 2022
31 janvier 2025
2022
Manoj Lalu (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions du programme Applications et Société
Lalu
Chercheur principal
Manoj Lalu
300 000
Engaging patients in laboratory-based cell therapy research: Co-production and field testing of a framework
QEJS, questions éthiques, juridiques et sociales
patient engagement, patient and public involvement, patient oriented research
Patient engagement in research is the meaningful and collaborative interaction between patients and researchers and can take place across all stages of research. It can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct and dissemination of research. While increasingly prevalent in clinical research, its application in preclinical (i.e., laboratory-based) research remains largely unrealized. We conducted a scoping review and found a paucity of published examples of patient engagement in basic research (and none in stem cell therapy). We have also conducted interviews with preclinical researchers and patients to identify barriers and enablers to patient engagement in preclinical laboratory research. Given the unique features of preclinical laboratory research (e.g. non-patient facing, technical nature) a framework for best-practices that facilitates patient engagement would be beneficial. This may be particularly appealing to SCN researchers as a means to increase public input and exposure. Our team, inclusive of patient partners, will develop an empirically derived and stakeholder informed framework outlining suggested methods to engage patient partners in preclinical stem cell research. The goals of this framework are to: i) provide step-by-step guidance on establishing patient researcher relationships, ii) provide general education and increase awareness of patient engagement (and highlight a common language needed), iii) provide information and guidance on activities, methods and considerations for patient engagement in preclinical research. Next, we will conduct field tests of the framework with multiple SCN funded labs. These groups (PIs, staff, trainees) will be paired with patient partners to implement and evaluate the framework. Our team will help facilitate these sessions. Participants and other stakeholders will then be invited to focus groups to identify gaps and refinements needed to the framework. These results will be used to create an optimized framework enriched with real-world examples and considerations specific to cell therapy and regenerative medicine research. This project will enable partnerships among patients and SCN researchers. Facilitating patient engagement in preclinical SCN research presents an exciting new opportunity to help realize the impact that patients can have.
1 avril 2022
31 janvier 2025
2023
Bruce Verchere (P)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Chercheur principal
Bruce Verchere, Francis Lynn, Megan Levings, Timothy Kieffer
188 000
Genetic engineering of hESC-derived insulin-producing cells to improve graft outcomes in type 1 diabetes
Diabète
human embryonic stem cells, beta cells, type 1 diabetes, insulin, transplantation, islet amyloid, chemokine, allograft rejection, CAR T cells, CRISPR.
A cure for type 1 diabetes may lie in the replacement of insulin-producing beta cells by transplantation. Hundreds of patients worldwide have received transplants of islets – clusters of insulin-producing beta cells in the pancreas – enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of beta cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. These cells have been transplanted into persons with type 1 diabetes in clinical trials (including in Vancouver), and have been shown to produce insulin. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function. We have established a team with complementary expertise in stem cell biology and regenerative medicine, diabetes and islet transplantation, and human immunology, and with previous SCN support have genetically engineered human embryonic stem cells, differentiated these cells into glucose-responsive, insulin-producing cells, and transplanted these cells in immune-deficient, diabetic mice. With new SCN support, we propose to further improve and refine this cell therapy approach and move it closer to clinical translation, by demonstrating that these, and additional, genetically engineered, stem-cell derived, human insulin-producing cells function better and survive longer following transplantation in pre-clinical models of type 1 diabetes. Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that could be tested in clinical trial in 5 years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 avril 2023
31 janvier 2025
2023
Francis Lynn (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Timothy Kieffer
188 000
Genetic engineering of hESC-derived insulin-producing cells to improve graft outcomes in type 1 diabetes
Diabète
human embryonic stem cells, beta cells, type 1 diabetes, insulin, transplantation, islet amyloid, chemokine, allograft rejection, CAR T cells, CRISPR.
A cure for type 1 diabetes may lie in the replacement of insulin-producing beta cells by transplantation. Hundreds of patients worldwide have received transplants of islets – clusters of insulin-producing beta cells in the pancreas – enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of beta cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. These cells have been transplanted into persons with type 1 diabetes in clinical trials (including in Vancouver), and have been shown to produce insulin. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function. We have established a team with complementary expertise in stem cell biology and regenerative medicine, diabetes and islet transplantation, and human immunology, and with previous SCN support have genetically engineered human embryonic stem cells, differentiated these cells into glucose-responsive, insulin-producing cells, and transplanted these cells in immune-deficient, diabetic mice. With new SCN support, we propose to further improve and refine this cell therapy approach and move it closer to clinical translation, by demonstrating that these, and additional, genetically engineered, stem-cell derived, human insulin-producing cells function better and survive longer following transplantation in pre-clinical models of type 1 diabetes. Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that could be tested in clinical trial in 5 years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 avril 2023
31 janvier 2025
2023
Megan Levings (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Timothy Kieffer
188 000
Genetic engineering of hESC-derived insulin-producing cells to improve graft outcomes in type 1 diabetes
Diabète
human embryonic stem cells, beta cells, type 1 diabetes, insulin, transplantation, islet amyloid, chemokine, allograft rejection, CAR T cells, CRISPR.
A cure for type 1 diabetes may lie in the replacement of insulin-producing beta cells by transplantation. Hundreds of patients worldwide have received transplants of islets – clusters of insulin-producing beta cells in the pancreas – enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of beta cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. These cells have been transplanted into persons with type 1 diabetes in clinical trials (including in Vancouver), and have been shown to produce insulin. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function. We have established a team with complementary expertise in stem cell biology and regenerative medicine, diabetes and islet transplantation, and human immunology, and with previous SCN support have genetically engineered human embryonic stem cells, differentiated these cells into glucose-responsive, insulin-producing cells, and transplanted these cells in immune-deficient, diabetic mice. With new SCN support, we propose to further improve and refine this cell therapy approach and move it closer to clinical translation, by demonstrating that these, and additional, genetically engineered, stem-cell derived, human insulin-producing cells function better and survive longer following transplantation in pre-clinical models of type 1 diabetes. Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that could be tested in clinical trial in 5 years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 avril 2023
31 janvier 2025
2023
Timothy Kieffer (C)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Verchere
Cochercheur
Bruce Verchere, Francis Lynn, Megan Levings, Timothy Kieffer
36 000
Genetic engineering of hESC-derived insulin-producing cells to improve graft outcomes in type 1 diabetes
Diabète
human embryonic stem cells, beta cells, type 1 diabetes, insulin, transplantation, islet amyloid, chemokine, allograft rejection, CAR T cells, CRISPR.
A cure for type 1 diabetes may lie in the replacement of insulin-producing beta cells by transplantation. Hundreds of patients worldwide have received transplants of islets – clusters of insulin-producing beta cells in the pancreas – enabling better blood glucose control without the need for insulin administration. Yet because there are not enough organ donors, new sources of beta cells are needed for the millions living with this disease. Moreover, most islet transplants fail within a few years, requiring patients to return to insulin injections. Two recent advances may transform cell therapy in diabetes. First, human insulin-producing cells can now be generated from stem cells in a laboratory dish within a few weeks. These cells have been transplanted into persons with type 1 diabetes in clinical trials (including in Vancouver), and have been shown to produce insulin. Second, the genes of cells can be engineered to produce proteins that may enhance their survival and function. We have established a team with complementary expertise in stem cell biology and regenerative medicine, diabetes and islet transplantation, and human immunology, and with previous SCN support have genetically engineered human embryonic stem cells, differentiated these cells into glucose-responsive, insulin-producing cells, and transplanted these cells in immune-deficient, diabetic mice. With new SCN support, we propose to further improve and refine this cell therapy approach and move it closer to clinical translation, by demonstrating that these, and additional, genetically engineered, stem-cell derived, human insulin-producing cells function better and survive longer following transplantation in pre-clinical models of type 1 diabetes. Our goal is to produce a new and improved cell source for cell replacement therapy in diabetes, that could be tested in clinical trial in 5 years. Such an advance could not only transform the lives of thousands of Canadians living with diabetes but also greatly reduce the tremendous economic and health burden that diabetes places on Canada today.
1 avril 2023
31 janvier 2025
2023
Véronique Moulin (P)
Université Laval
Subventions de soutien à l’accélération de la transposition clinique
Skin autografts are the standard treatment of burn wounds. When burns cover more than 50% of the total body surface area, the availability of donor sites is considerably reduced. We developed a tissue engineering method to produce autologous Self-Assembled Skin Substitutes (SASS) from small skin biopsy and used them to permanently cover full-thickness wounds. A multicenter early phase clinical trial is ongoing with patients enrolled from Canadian burn units. However, the delay for SASS production is the main limitation of this treatment. Our long-term aim is to accelerate SASS production. Our strategy is based on preclinical results showing that allogeneic fibroblasts are not immunogenic in contrast to keratinocytes which are promptly rejected. The objective of this proposal is to produce a GMP fibroblast bank in order to avoid isolating and growing fibroblasts from each patient, a step that lasts in mean 17 days. The already banked allogeneic fibroblasts (A) will then be used with autologous keratinocytes (a) to produce AaSASS. To produce the cell bank, fibroblasts isolated from the dermis of healthy newborns will be expanded in culture according to GMP. The cell population taking the shortest time to reconstruct a dermis will be selected for expansion and production of the GMP master cell bank and working cell banks. The bank will be tested for its biosafety throughout the process. We evaluate that this new method will allow to graft AsSASS after 4 weeks compared with the autologous SASS that can only be grafted after at least 8 weeks. In parallel, the preparation of the documentation necessary for the pre-CTA consultation meeting with Health Canada to start a clinical trial testing AaSASS will be initiated (protocol synopsis, consent form, clinical protocol, investigator's brochure, quality information, etc.). Our interdisciplinary team is composed of four internationally renowned researchers in regenerative medicine from two universities. We are the only Canadian team dedicated to the reconstruction of tissues having expertise, highly qualified personnel and facilities ensuring the production and clinical translation of AaSASS. The production of an allogeneic fibroblast biobank is the first step to produce AsSASS satisfying applicable Federal regulatory requirements, which will eventually improve and reduce hospital length of stay of burn patients.
1 avril 2023
31 janvier 2025
2023
Ma'n Zawati (C)
McGill University
Subventions de soutien à l’accélération de la transposition clinique
Skin autografts are the standard treatment of burn wounds. When burns cover more than 50% of the total body surface area, the availability of donor sites is considerably reduced. We developed a tissue engineering method to produce autologous Self-Assembled Skin Substitutes (SASS) from small skin biopsy and used them to permanently cover full-thickness wounds. A multicenter early phase clinical trial is ongoing with patients enrolled from Canadian burn units. However, the delay for SASS production is the main limitation of this treatment. Our long-term aim is to accelerate SASS production. Our strategy is based on preclinical results showing that allogeneic fibroblasts are not immunogenic in contrast to keratinocytes which are promptly rejected. The objective of this proposal is to produce a GMP fibroblast bank in order to avoid isolating and growing fibroblasts from each patient, a step that lasts in mean 17 days. The already banked allogeneic fibroblasts (A) will then be used with autologous keratinocytes (a) to produce AaSASS. To produce the cell bank, fibroblasts isolated from the dermis of healthy newborns will be expanded in culture according to GMP. The cell population taking the shortest time to reconstruct a dermis will be selected for expansion and production of the GMP master cell bank and working cell banks. The bank will be tested for its biosafety throughout the process. We evaluate that this new method will allow to graft AsSASS after 4 weeks compared with the autologous SASS that can only be grafted after at least 8 weeks. In parallel, the preparation of the documentation necessary for the pre-CTA consultation meeting with Health Canada to start a clinical trial testing AaSASS will be initiated (protocol synopsis, consent form, clinical protocol, investigator's brochure, quality information, etc.). Our interdisciplinary team is composed of four internationally renowned researchers in regenerative medicine from two universities. We are the only Canadian team dedicated to the reconstruction of tissues having expertise, highly qualified personnel and facilities ensuring the production and clinical translation of AaSASS. The production of an allogeneic fibroblast biobank is the first step to produce AsSASS satisfying applicable Federal regulatory requirements, which will eventually improve and reduce hospital length of stay of burn patients.
1 avril 2023
31 janvier 2025
2023
Chanel Beaudoin-Cloutier (C)
Université Laval
Subventions de soutien à l’accélération de la transposition clinique
Skin autografts are the standard treatment of burn wounds. When burns cover more than 50% of the total body surface area, the availability of donor sites is considerably reduced. We developed a tissue engineering method to produce autologous Self-Assembled Skin Substitutes (SASS) from small skin biopsy and used them to permanently cover full-thickness wounds. A multicenter early phase clinical trial is ongoing with patients enrolled from Canadian burn units. However, the delay for SASS production is the main limitation of this treatment. Our long-term aim is to accelerate SASS production. Our strategy is based on preclinical results showing that allogeneic fibroblasts are not immunogenic in contrast to keratinocytes which are promptly rejected. The objective of this proposal is to produce a GMP fibroblast bank in order to avoid isolating and growing fibroblasts from each patient, a step that lasts in mean 17 days. The already banked allogeneic fibroblasts (A) will then be used with autologous keratinocytes (a) to produce AaSASS. To produce the cell bank, fibroblasts isolated from the dermis of healthy newborns will be expanded in culture according to GMP. The cell population taking the shortest time to reconstruct a dermis will be selected for expansion and production of the GMP master cell bank and working cell banks. The bank will be tested for its biosafety throughout the process. We evaluate that this new method will allow to graft AsSASS after 4 weeks compared with the autologous SASS that can only be grafted after at least 8 weeks. In parallel, the preparation of the documentation necessary for the pre-CTA consultation meeting with Health Canada to start a clinical trial testing AaSASS will be initiated (protocol synopsis, consent form, clinical protocol, investigator's brochure, quality information, etc.). Our interdisciplinary team is composed of four internationally renowned researchers in regenerative medicine from two universities. We are the only Canadian team dedicated to the reconstruction of tissues having expertise, highly qualified personnel and facilities ensuring the production and clinical translation of AaSASS. The production of an allogeneic fibroblast biobank is the first step to produce AsSASS satisfying applicable Federal regulatory requirements, which will eventually improve and reduce hospital length of stay of burn patients.
1 avril 2023
31 janvier 2025
2023
Lucie Germain (C)
Université Laval
Subventions de soutien à l’accélération de la transposition clinique
Skin autografts are the standard treatment of burn wounds. When burns cover more than 50% of the total body surface area, the availability of donor sites is considerably reduced. We developed a tissue engineering method to produce autologous Self-Assembled Skin Substitutes (SASS) from small skin biopsy and used them to permanently cover full-thickness wounds. A multicenter early phase clinical trial is ongoing with patients enrolled from Canadian burn units. However, the delay for SASS production is the main limitation of this treatment. Our long-term aim is to accelerate SASS production. Our strategy is based on preclinical results showing that allogeneic fibroblasts are not immunogenic in contrast to keratinocytes which are promptly rejected. The objective of this proposal is to produce a GMP fibroblast bank in order to avoid isolating and growing fibroblasts from each patient, a step that lasts in mean 17 days. The already banked allogeneic fibroblasts (A) will then be used with autologous keratinocytes (a) to produce AaSASS. To produce the cell bank, fibroblasts isolated from the dermis of healthy newborns will be expanded in culture according to GMP. The cell population taking the shortest time to reconstruct a dermis will be selected for expansion and production of the GMP master cell bank and working cell banks. The bank will be tested for its biosafety throughout the process. We evaluate that this new method will allow to graft AsSASS after 4 weeks compared with the autologous SASS that can only be grafted after at least 8 weeks. In parallel, the preparation of the documentation necessary for the pre-CTA consultation meeting with Health Canada to start a clinical trial testing AaSASS will be initiated (protocol synopsis, consent form, clinical protocol, investigator's brochure, quality information, etc.). Our interdisciplinary team is composed of four internationally renowned researchers in regenerative medicine from two universities. We are the only Canadian team dedicated to the reconstruction of tissues having expertise, highly qualified personnel and facilities ensuring the production and clinical translation of AaSASS. The production of an allogeneic fibroblast biobank is the first step to produce AsSASS satisfying applicable Federal regulatory requirements, which will eventually improve and reduce hospital length of stay of burn patients.
1 avril 2023
31 janvier 2025
2023
Juan Carlos Zúñiga-Pflücker (P)
Sunnybrook Research Institute
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Chercheur principal
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
407 375
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTIMM)
Immunothérapie; cancer
Immunodeficiency, Blood stem cells, Bone marrow translansplant, Thymic reconstitution, T cells, Cancer treatment
Current treatments for cancer patients receiving a hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most blood cell subsets recover quickly, T-cells, which are a key component of the immune system, remain absent or at low levels for months to years. This state of immunodeficiency in T-cells increases susceptibility to relapse and opportunistic infections. To help address these adverse effects, lengthy treatment with antibiotics and antivirals, and in some cases infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease (GvHD), which can lead to organ failure and death. Therefore, complications due to a lack of T-cells resulting in immunodeficiency or the presence of donor T-cells causing GvHD adversely affect and complicate treatment outcomes. To provide patients with a much-needed T-cell regeneration or boost, while avoiding GVHD, we developed a novel way of generating progenitor T-cells (proTs) from donor blood stem cells in culture. We recently optimized this method to produce large numbers of proTs, reducing the limitation posed by the rarity of blood stem cells that are at the same time required for bone marrow reconstitution. In addition, we successfully started the scale up production of proTs, from culture dishes to bioreactor vessels that are compatible with clinical practices. This method will help speed the reemergence of T-cells in post-transplant patients, as adoptively-transferred proT cells engraft the thymus and further differentiate into mature T-cells. ProT-cells also have the effect of thymic repair after its injury due to earlier chemo/radiation treatment. Importantly, in addition to conferring immunity, emerging T-cells would also be host tolerant and hence not cause GvHD, as self-reactive T-cells are eliminated in the thymus through negative selection. Preclinical studies in animal models have demonstrated that provision of proT-cells following chemotherapy and radiation treatment provide an immune boost that is an effective and potentially curative cell therapy. Our work will enable proT-cells to improve the quality of life of HSCT patients by decreasing their susceptibility to infections and relapse, while preventing GVHD, as new T cells are rapidly regenerated.
1 avril 2023
31 janvier 2025
2023
Donna Wall (C)
Hospital for Sick Children
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Cochercheur
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
101 500
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTIMM)
Immunothérapie; cancer
Immunodeficiency, Blood stem cells, Bone marrow translansplant, Thymic reconstitution, T cells, Cancer treatment
Current treatments for cancer patients receiving a hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most blood cell subsets recover quickly, T-cells, which are a key component of the immune system, remain absent or at low levels for months to years. This state of immunodeficiency in T-cells increases susceptibility to relapse and opportunistic infections. To help address these adverse effects, lengthy treatment with antibiotics and antivirals, and in some cases infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease (GvHD), which can lead to organ failure and death. Therefore, complications due to a lack of T-cells resulting in immunodeficiency or the presence of donor T-cells causing GvHD adversely affect and complicate treatment outcomes. To provide patients with a much-needed T-cell regeneration or boost, while avoiding GVHD, we developed a novel way of generating progenitor T-cells (proTs) from donor blood stem cells in culture. We recently optimized this method to produce large numbers of proTs, reducing the limitation posed by the rarity of blood stem cells that are at the same time required for bone marrow reconstitution. In addition, we successfully started the scale up production of proTs, from culture dishes to bioreactor vessels that are compatible with clinical practices. This method will help speed the reemergence of T-cells in post-transplant patients, as adoptively-transferred proT cells engraft the thymus and further differentiate into mature T-cells. ProT-cells also have the effect of thymic repair after its injury due to earlier chemo/radiation treatment. Importantly, in addition to conferring immunity, emerging T-cells would also be host tolerant and hence not cause GvHD, as self-reactive T-cells are eliminated in the thymus through negative selection. Preclinical studies in animal models have demonstrated that provision of proT-cells following chemotherapy and radiation treatment provide an immune boost that is an effective and potentially curative cell therapy. Our work will enable proT-cells to improve the quality of life of HSCT patients by decreasing their susceptibility to infections and relapse, while preventing GVHD, as new T cells are rapidly regenerated.
1 avril 2023
31 janvier 2025
2023
Jonas Mattsson (C)
University Health Network
Subventions de soutien à l’accélération de la transposition clinique
Zuniga-Pflucker
Cochercheur
Juan Carlos Zúñiga-Pflücker, Donna Wall, Jonas Mattsson
91 000
Production of progenitor T cells for immune-reconstitution and targeted immunotherapies (ProTIMM)
Immunothérapie; cancer
Immunodeficiency, Blood stem cells, Bone marrow translansplant, Thymic reconstitution, T cells, Cancer treatment
Current treatments for cancer patients receiving a hematopoietic stem cell transplant (HSCT) involve the use of chemotherapy and/or radiation. While most blood cell subsets recover quickly, T-cells, which are a key component of the immune system, remain absent or at low levels for months to years. This state of immunodeficiency in T-cells increases susceptibility to relapse and opportunistic infections. To help address these adverse effects, lengthy treatment with antibiotics and antivirals, and in some cases infusion of donor T-cells are required. However, donor T-cells may also attack healthy tissues and cause graft-versus-host disease (GvHD), which can lead to organ failure and death. Therefore, complications due to a lack of T-cells resulting in immunodeficiency or the presence of donor T-cells causing GvHD adversely affect and complicate treatment outcomes. To provide patients with a much-needed T-cell regeneration or boost, while avoiding GVHD, we developed a novel way of generating progenitor T-cells (proTs) from donor blood stem cells in culture. We recently optimized this method to produce large numbers of proTs, reducing the limitation posed by the rarity of blood stem cells that are at the same time required for bone marrow reconstitution. In addition, we successfully started the scale up production of proTs, from culture dishes to bioreactor vessels that are compatible with clinical practices. This method will help speed the reemergence of T-cells in post-transplant patients, as adoptively-transferred proT cells engraft the thymus and further differentiate into mature T-cells. ProT-cells also have the effect of thymic repair after its injury due to earlier chemo/radiation treatment. Importantly, in addition to conferring immunity, emerging T-cells would also be host tolerant and hence not cause GvHD, as self-reactive T-cells are eliminated in the thymus through negative selection. Preclinical studies in animal models have demonstrated that provision of proT-cells following chemotherapy and radiation treatment provide an immune boost that is an effective and potentially curative cell therapy. Our work will enable proT-cells to improve the quality of life of HSCT patients by decreasing their susceptibility to infections and relapse, while preventing GVHD, as new T cells are rapidly regenerated.
1 avril 2023
31 janvier 2025
2023
Bernard Thébaud (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien à l’accélération de la transposition clinique
The major impact of the AAVenger B project will be the efficient, accelerated, evidence-based translation of a novel, potentially life-saving gene therapy for newborns with surfactant protein deficiencies. Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation. Novel therapies for surfactant deficiencies are urgently needed. We have engineered a novel AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function, and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls. Here, we propose a clinical accelerator program to (i) perform feasibility, safety and efficacy studies of AAV-SP-B in a neonatal piglet model; (ii) perform systematic reviews and meta-analyses on preclinical studies and clinical studies of gene therapy for neonatal lung diseases; (iii) perform an early economic evaluation of AAV therapy for neonatal SP-B deficiency to estimate the potential therapeutic “headroom” and price ceiling for this therapy; and (iv) identify barriers and facilitators among parents and physicians to conducting a gene therapy clinical trial in neonates to optimize the clinical trial design. The herein proposed experiments will accelerate the clinical translation of this potentially life-saving gene therapy by generating critical data for regulatory approval and enabling the delivery of a CTA to Health Canada using the same successful approach that has led to our current cell therapy trial (NCT04255147).
1 avril 2023
31 janvier 2025
2023
Dean Fergusson (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien à l’accélération de la transposition clinique
The major impact of the AAVenger B project will be the efficient, accelerated, evidence-based translation of a novel, potentially life-saving gene therapy for newborns with surfactant protein deficiencies. Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation. Novel therapies for surfactant deficiencies are urgently needed. We have engineered a novel AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function, and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls. Here, we propose a clinical accelerator program to (i) perform feasibility, safety and efficacy studies of AAV-SP-B in a neonatal piglet model; (ii) perform systematic reviews and meta-analyses on preclinical studies and clinical studies of gene therapy for neonatal lung diseases; (iii) perform an early economic evaluation of AAV therapy for neonatal SP-B deficiency to estimate the potential therapeutic “headroom” and price ceiling for this therapy; and (iv) identify barriers and facilitators among parents and physicians to conducting a gene therapy clinical trial in neonates to optimize the clinical trial design. The herein proposed experiments will accelerate the clinical translation of this potentially life-saving gene therapy by generating critical data for regulatory approval and enabling the delivery of a CTA to Health Canada using the same successful approach that has led to our current cell therapy trial (NCT04255147).
1 avril 2023
31 janvier 2025
2023
Justin Presseau (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions de soutien à l’accélération de la transposition clinique
The major impact of the AAVenger B project will be the efficient, accelerated, evidence-based translation of a novel, potentially life-saving gene therapy for newborns with surfactant protein deficiencies. Air sacs deep in the lung called alveoli are coated with surfactant. Surfactant keeps alveoli open to ensure efficient exchange of oxygen and waste carbon dioxide. Surfactant is produced by progenitor cells in the deep lung (type 2 alveolar epithelial cells, AT2). Surfactant proteins (such as SP-B, SP-C) or surfactant-associated ABCA3 are critical for normal lung function. Mutations in these surfactant protein genes cause severe failure to breathe at birth and are invariably lethal. More of these genetic lung diseases that declare themselves later in life in children and young adults are increasingly recognized and result in debilitating interstitial lung diseases (lung scarring) due to destruction of AT2 cells. The only treatment option is lung transplantation. Novel therapies for surfactant deficiencies are urgently needed. We have engineered a novel AAV capsid, with unprecedented efficiency in targeting the necessary AT2 lung stem/progenitor cells to deliver a normal copy of the SP-B gene and enable disease correction. Airway delivery of AAV-SP-B in deficient mice restores SP-B expression, improves lung injury and function, and dramatically enhances survival to up to 6 months compared to 3-4 days in untreated controls. Here, we propose a clinical accelerator program to (i) perform feasibility, safety and efficacy studies of AAV-SP-B in a neonatal piglet model; (ii) perform systematic reviews and meta-analyses on preclinical studies and clinical studies of gene therapy for neonatal lung diseases; (iii) perform an early economic evaluation of AAV therapy for neonatal SP-B deficiency to estimate the potential therapeutic “headroom” and price ceiling for this therapy; and (iv) identify barriers and facilitators among parents and physicians to conducting a gene therapy clinical trial in neonates to optimize the clinical trial design. The herein proposed experiments will accelerate the clinical translation of this potentially life-saving gene therapy by generating critical data for regulatory approval and enabling the delivery of a CTA to Health Canada using the same successful approach that has led to our current cell therapy trial (NCT04255147).
1 avril 2023
31 janvier 2025
2023
Peter Zandstra (P)
University of British Columbia
Subventions de soutien à l’accélération de la transposition clinique
Zandstra
Chercheur principal
Peter Zandstra, Yale Michaels
218 034
PSC-derived immune cells as an advanced delivery vehicle for protein therapeutics
Produits thérapeutiques à base de protéines
Stem cells, B cells, inflammation, synthetic biology, developmental immunology
Proteins are powerful therapeutic agents and a rapidly growing market. Despite revolutionising treatment of cancer, autoimmunity and blood disease, protein therapies have important limitations. Many biologics are dosed via recurrent injections. This causes pain, poor patient compliance and high costs. Delivery by injection also leads to systemic distribution of the therapy. This decreases the effective dose at the diseased tissue and increases the dose at healthy off-target tissues leading to side effects. To solve these delivery challenges, Apiary Therapeutics (Tx) a recently founded Canadian company, aims to use living cells as autonomous delivery vehicles for biologics. By making these cellular protein factories from human pluripotent stem cells (hPSCs), Apiary Tx will enable a renewable, low-cost, off-the-shelf product. Using synthetic biology, Apiary Tx will engineer these cells to secrete protein therapeutics specifically at the time, location and dosage that is optimal for a specific indication, enhancing safety and efficacy. B cells are ideal for in vivo protein delivery. They are naturally capable of secreting large quantities of antibodies and can persist in the body for decades, providing long-term protection from pathogens. We will re-purpose these attributes and engineer B cells to express and secrete protein therapeutics in the body. The first objective of the proposal (led by Zandstra and Vento-Tormo) is to develop chemically defined (feeder and serum-free) conditions for differentiating B cells from hPSCs. This will be achieved using model-guided multi-factor media screening. We will also apply CellPhoneDB (developed by Vento-Tormo) to computationally predict molecules that will enhance B cell differentiation. The second objective of the proposal (led by Michaels) is to develop a sense-and-response system to enable controlled expression of a protein payload specifically within a target tissue of interest. We will trial synthetic receptors and microRNA-controlled gene circuits to control expression of a mock luciferase payload. Deliverables: GMP-compatible, off-the-shelf B cell production and a method for delivering protein therapies safely to diseased tissues. This project will pave the way for pre-clinical testing of Apiary Tx’s first pipeline candidates and significantly de-risk the company’s commercial viability.
1 avril 2023
31 janvier 2025
2023
Yale Michaels (C)
CancerCare Manitoba
Subventions de soutien à l’accélération de la transposition clinique
Zandstra
Cochercheur
Peter Zandstra, Yale Michaels
181 966
PSC-derived immune cells as an advanced delivery vehicle for protein therapeutics
Produits thérapeutiques à base de protéines
Stem cells, B cells, inflammation, synthetic biology, developmental immunology
Proteins are powerful therapeutic agents and a rapidly growing market. Despite revolutionising treatment of cancer, autoimmunity and blood disease, protein therapies have important limitations. Many biologics are dosed via recurrent injections. This causes pain, poor patient compliance and high costs. Delivery by injection also leads to systemic distribution of the therapy. This decreases the effective dose at the diseased tissue and increases the dose at healthy off-target tissues leading to side effects. To solve these delivery challenges, Apiary Therapeutics (Tx) a recently founded Canadian company, aims to use living cells as autonomous delivery vehicles for biologics. By making these cellular protein factories from human pluripotent stem cells (hPSCs), Apiary Tx will enable a renewable, low-cost, off-the-shelf product. Using synthetic biology, Apiary Tx will engineer these cells to secrete protein therapeutics specifically at the time, location and dosage that is optimal for a specific indication, enhancing safety and efficacy. B cells are ideal for in vivo protein delivery. They are naturally capable of secreting large quantities of antibodies and can persist in the body for decades, providing long-term protection from pathogens. We will re-purpose these attributes and engineer B cells to express and secrete protein therapeutics in the body. The first objective of the proposal (led by Zandstra and Vento-Tormo) is to develop chemically defined (feeder and serum-free) conditions for differentiating B cells from hPSCs. This will be achieved using model-guided multi-factor media screening. We will also apply CellPhoneDB (developed by Vento-Tormo) to computationally predict molecules that will enhance B cell differentiation. The second objective of the proposal (led by Michaels) is to develop a sense-and-response system to enable controlled expression of a protein payload specifically within a target tissue of interest. We will trial synthetic receptors and microRNA-controlled gene circuits to control expression of a mock luciferase payload. Deliverables: GMP-compatible, off-the-shelf B cell production and a method for delivering protein therapies safely to diseased tissues. This project will pave the way for pre-clinical testing of Apiary Tx’s first pipeline candidates and significantly de-risk the company’s commercial viability.
1 avril 2023
31 janvier 2025
2023
Sowmya Viswanathan (P)
University Health Network
Subventions de soutien des essais cliniques
Viswanathan
Chercheur principal
Sowmya Viswanathan
750 000
Autologous Bone Marrow Aspirate Concentrate or Lipoaspirate Concentrate for OsteoArthritis: ABLE OA Clinical Trial
Osteoarthritis (OA) is a leading cause of morbidity and disability affecting 1 in 6 Canadians and 1 in 4 by 2040 resulting in high economic burden. Despite decades of research, there is no disease modifying therapies, and there is an urgent and growing need for non-surgical interventions. Autologous minimally manipulated cellular preparations (bone marrow aspirate concentrate (BMAC) and lipoaspirate concentrate (LAC)) have long been used in musculoskeletal conditions demonstrating extensive safety and moderate efficacy. Both concentrates contain mesenchymal stromal cells, hematopoietic stem cells, endothelial cells, which together produce beneficial analgesic and functional effects based on secretion of paracrine factors that modulate inflammation, angiogenesis and support endogenous progenitor proliferation and differentiation. This has been shown in numerous animal studies; however, clinical results are conflicting due to heterogeneity in processing, clinical endpoints, target patient population and clinical trial biases. This led Health Canada to clarify regulations on autologous minimally manipulated cell preparations as drugs requiring their evaluation in clinical trials. The Canadian Orthopedic Association also recommends “rigorous, well-designed clinical trials . . .(to) establish the safety, efficacy, and cost-effectiveness prior to widespread adoption”. Accordingly, we are conducting a Health Canada-authorized phase II/III clinical trial using BMAC and LAC to treat knee OA that addresses 2 gaps: i) mixed clinical efficacy, based on non-controlled, single-centre trials preventing market authorization in Canada under current drug regulations; and, ii) heterogeneity in patient responsiveness that is currently non-predictable and contributes to overall mixed efficacy. To address the first gap, a multi-centred, randomized, double-blinded, placebo-controlled trial will assess clinically relevant changes in pain and function outcomes in a non-biased manner. To address the second gap, the profiling of patient immune and inflammatory status will occur to evaluate individual heterogeneity in responses. Results will inform clinical practice and policy decisions i.e., the use of a new regulatory pathway for potential market authorization.
1 avril 2023
31 janvier 2025
2023
Marc Jeschke (P)
McMaster University
Subventions de soutien des essais cliniques
Jeschke
Chercheur principal
Marc Jeschke
298 000
A phase I, single-blind, randomized study of safety of cellularized Integra® using autologous burn-derived MSCs
Acute, complex acute, and chronic wounds represent an increasing public health issue. Early wound closure can not only be lifesaving, for example for burn patients, but can drastically improve patients’ quality of life by reducing the sequelae of debilitating scars. Strategies to regenerate skin and enhance wound healing have evolved from a novelty to necessity. While autologous skin grafts cover minor burns, this approach is particularly challenging in significant burns with limited donor site availability. Alternatively, Integra®, a temporary bi-layered substitute composed of a bovine collagen-based dermal analog and a temporary epidermal silicone sheet, has been shown to promote skin regeneration. Although Integra® shows promising results as a temporary skin substitute, it lacks the cellular components of skin and relies on the response of the body to infiltrate cells into the scaffold. Hence, this results in impermanent and ineffective wound closure. With the promising effect of stem cells on wound healing, adding stem cells into the Integra® scaffold might solve this challenge. We recently made a sentinel discovery that debrided burn skin contains viable cells that are multipotent and demonstrate characteristics of human mesenchymal stem cells (MSCs) termed as burn-derived MSCs (BDMSCs). This is exciting since this autologous source of stem cells can be isolated from the burn tissue that is routinely excised, discarded, and considered medical waste. Therefore, we propose to engineer an autologous skin replacement for permanent wound coverage that will biologically integrate a collagen matrix from Integra® with a patient’s autologous BDMSCs. This autologous stem cell incorporated matrix, Integra-SC, will enable complete wound closure and effective regeneration. The overall objective is to test Integra-SC in a randomized controlled phase I clinical trial in burn patients. We hypothesize that Integra®-SC will provide an effective, scalable, and immunologically compatible skin substitute improving wound healing and mitigating scar formation for burn patients. We will test our hypothesis by comparing matched areas of the body treated using acellular Integra® (control) vs cellularized Integra®-SC (treatment). The aims of this project are: 1) safety (primary outcome); 2) time of wound healing; 3) quality of skin regeneration; and 4) extent of scar formation.
1 avril 2023
31 janvier 2025
2023
Lucie Germain (P)
Université Laval
Subventions de soutien des essais cliniques
Germain
Chercheur principal
Lucie Germain
603 600
Clinical trial of cultured epithelial corneal autografts for the treatment of Canadians with limbal stem cell deficiency
Maladie des yeux, maladies des yeux; maladie oculaire
Limbal stem cell deficiency (LSCD) is a severe disease characterised by the depletion of corneal stem cells in the limbus of the eye due to trauma or pathology. Without limbal stem cells, the epithelium is unable to heal. This results in chronic inflammation and the invasion of the cornea by the conjunctiva and its blood vessels, which leads to corneal opacification and severe vision loss in 64% of patients and chronic ocular pain. The standard treatment consists in transplanting substantial amounts of tissue from the unaffected contralateral eye, which has the potential to induce LSCD in the healthy donor eye. At the LOEX/CHU de Québec-Université Laval (CHU), one of the leading organ reconstruction laboratories in the world, we have set up cultured epithelial corneal autografts (CECA), a tissue-engineered autologous construct produced from corneal limbal stem cells expanded on a human fibroblast feeder layer. The aim of this proposal is to continue our ongoing multicenter clinical trial to demonstrate that CECA is an efficient strategy to treat patients suffering from LSCD. Twelve additional LSCD patients will be recruited and treated with CECA, with primary study endpoint focused on efficacy and collecting more safety data. To properly estimate the success/failure rate, a total of 49 adults and 5 children will have to be recruited for this study overall. Deliverables: 1) Patient recruitment at 3 sites: CUO-CHU, Québec; CUO-UdeM, Montréal; and University Health Network, Toronto Western Hospital, UofT, Toronto; 2) CECA grafting and data collection; and 3) follow-up of the 12 recruited study patients. Our team of scientific researchers (Germain, Moulin), clinicians (Bazin, Brunette, Chan, Kyrillos, Slomovic), economic (Guertin) and ethical/legal experts (Zawati, Knoppers) will continue the clinical trial they initiated in 2012; the first trial in Canada to offer CECA as a treatment for LSCD. IMPACT: Being the first in Canada, CECA shows promise as a new cell therapy which could be accessible to Canadian ophthalmologists and their patients for the treatment of LSCD. Without treatment, vision loss can generate significant limitations with life-long consequences on the quality of life of patients and their families. This innovative regenerative medicine treatment can change the lives of LSCD patients by restoring sight in the affected eye.
1 avril 2023
31 janvier 2025
2023
Michael Fehlings (P)
University Health Network
Subventions de soutien aux partenariats biotechnologiques
Fehlings
Chercheur principal
Michael Fehlings
400 000
Translation of cGMP grade oligodenrogenic NPCs (oNPCs) for the treatment of traumatic cervical spinal cord injury
Lésion de la moelle épinière
neural stem cells, hiPSC, GMP, spinal cord injury
The Fehlings laboratory in collaboration with Inteligex Inc has generated a unique platform-based cell therapy system for the treatment of CNS disorders. Our lead indication is traumatic cervical SCI (cSCI) which results in devastating long-term physical, social, and financial impacts on patients and their families. Currently, there are no effective regenerative therapies for SCI. However, cSCI is a prime candidate for regenerative medicine due to an extensive understanding of the pathophysiology of the disease and in the case of chronic SCI the non-progressive stable pathology. Inteligex has generated the cutting-edge oNPC (oligodendrogenic biased neural progenitor cells; Intelicells) platform a human iPSC-based cell therapy. The oNPC platform comprises of an allogenic iPSC cGMP backbone together with regionally programmed neural stem cells that have been lineaglineage-biased maintaining tripotency. The key aim of the oNPC platform is to restore lost function in CNS disorders. This proposal focuses on oNPC cells for the treatment of acute and chronic traumatic cSCI. Pre-clinical data with research-grade human iPSC cells has demonstrated strong evidence that oNPC transplantation results in significant restoration of motor function in both acute and chronic forms of traumatic cSCI. The use of human iPSC cells that display regional identity in addition to biasing towards the oligodendrocytic lineage represents a significant advantage over our competitors who use embryonic-derived spinal cells that do not possess a cervical identity and do not maintain tripotency. Inteligex has produced cGMP clinical grade oNPC cells that have been extensively characterized and meet current FDA requirements. The aim of this proposal is to translate oNPCs for the treatment of acute and chronic cSCI. This project will comprise the following aims 1) validation of cGMP clinical grade human oNPC cells to restore lost function following traumatic acute and chronic cSCI. 2) Determine a safety and toxicity profile for oNPC Repair cells in porcine. 3) Determine the optimal transplantation and immunosuppression protocol for the clinical use of oNPC Repair cells in porcine. This work will form the basis of an application to Health Canada and the FDA for the testing of ONPC Repair Cells in clinical trials.
1 avril 2023
31 janvier 2025
2023
C. Florian Bentzinger (P)
Université de Sherbrooke
Subventions de soutien aux partenariats biotechnologiques
Bentzinger
Chercheur principal
C. Florian Bentzinger
398 600
Mobilizing endogenous repair in muscular dystrophy
Muscular dystrophies (MDs) are rare genetic diseases that frequently affect children and are often accompanied by skeletal muscle wasting leading to premature death. Most mutations causing MD lead to cycles of muscle fiber de- and regeneration, which become progressively inefficient resulting in an accumulation of scar tissue. Presently no effective treatment options are available for MD. The diversity and heterogeneity of mutations causing MD poses a major challenge for the development and manufacturing of genome targeted therapeutics. Therefore, mutation-independent treatment approaches that are applicable to a broad spectrum of MD patients represent an important therapeutic opportunity. We postulate that the increasingly recognized concept of stimulation of “endogenous repair” represents such an approach. The underlying hypothesis is that, independent of the respective mutations or affected genes, enhancing or restoring the regenerative function of endogenous muscle stem cells (MuSCs) in MD, would allow to preserve skeletal muscles for a longer time in a state allowing for efficient self-repair. Importantly, we recently demonstrated that MuSC function is severely affected in MDs caused by mutations in the dystrophin (Duchenne), laminin alpha-2 (LAMA2), and collagen 6 (Col6) genes. The compound SAT732 by Satellos Biosciences stimulates a pathway that is involved in controlling asymmetric MuSC divisions, which have been shown to be impaired in Duchenne MD due to a loss of cell polarity caused by the absence of dystrophin. Dystrophin is associated with a receptor complex in the MuSC plasma membrane, which in turn is linked to the LAMA2 and Col6 in the extracellular space, suggesting a common disease mechanism affecting cell polarity. While testing in Col6 deficient mice is ongoing, our preliminary data shows that SAT732 is highly effective in LAMA2 MD and leads to dramatic increases in muscle strength. Here we propose to I) continue our preclinical characterization of the effect of SAT732 in LAMA2 and Col6 MD, II) perform an in-depth analysis of the molecular effects of this drug on MuSCs in these two diseases, II) and test whether it synergizes with other experimental therapies. Our proposal will advance the preclinical characterization of a much-needed and highly efficient mutation-independent drug that is effective across multiple forms of MD.
1 avril 2023
31 janvier 2025
2023
Massimiliano Paganelli (P)
Centre Hospitalier Universitaire Sainte-Justine
Subventions de soutien aux partenariats biotechnologiques
Paganelli
Chercheur principal
Massimiliano Paganelli, Christopher Rose
320 000
iPSC-derived Encapsulated Liver Tissue: extending the indication to acute-on-chronic liver failure
Maladies du foie, maladie du foie, maladie hépatique
With the support of the Stem Cell Network, we have developed a new cell therapy for the treatment of liver failure. By combining induced pluripotent stem cell-derived liver organoids with finely tuned biomaterials, we generated an innovative regenerative medicine product (the encapsulated liver tissue, ELT) that proved capable to treat acute liver failure (ALF) in immunocompetent mice, improving survival, treating hepatic encephalopathy (HE) and accelerating liver regeneration, without the need for immunosuppression and being explanted once the recipient’s own liver regenerated. We filed 3 patents and span off a regenerative medicine company, Morphocell Technologies, which is now helping us bring the ELT to the clinic as an allogeneic therapy for ALF. The company is on schedule to file for a CTA/IND within the next 3 years. With Morphocell, we recently confirmed the feasibility, safety and proof-of-concept efficacy of implanting a clinical-scale ELT in a swine model of ALF. All data show that the ELT has a significant competitive advantage over competing approaches and is a promising first-in-class treatment for ALF. With the project proposed here, we aim at validating the safety and efficacy of the ELT for the treatment of acute-on-chronic liver failure (ACLF). As severe as ALF but developing in patients with underlying chronic liver disease, ACLF represents an unmet health need (>30,000 cases per year in North America, 50% mortality rate, >$18B global market). With the aim of extending the indication of the ELT to the treatment of ACLF, we partner with Morphocell to assess how the ELT behaves faced with ACLF’s inflammatory environment, the presence of ascites, and a reduced liver regeneration potential. We will assess the effect of inflammatory cytokines on the ELT and measure its functions in vivo at longer term. We will then evaluate its efficacy on survival, HE and liver regeneration in mouse and rat models of ACLF. The safety of the implant and the impact of the inflammatory environment and portal hypertension on rejection and the ELT survival and functions will be studied, together with the feasibility of explanting it once the decompensation resolved. Overall, this project will allow generating strong data in support of an expansion of the indication of the ELT to ACLF in view of upcoming discussions with regulators for approaching clinical phases.
1 avril 2023
31 janvier 2025
2023
Christopher Rose (C)
Centre Hospitalier de l'Université de Montréal
Subventions de soutien aux partenariats biotechnologiques
Paganelli
Cochercheur
Massimiliano Paganelli, Christopher Rose
80 000
iPSC-derived Encapsulated Liver Tissue: extending the indication to acute-on-chronic liver failure
Maladies du foie, maladie du foie, maladie hépatique
With the support of the Stem Cell Network, we have developed a new cell therapy for the treatment of liver failure. By combining induced pluripotent stem cell-derived liver organoids with finely tuned biomaterials, we generated an innovative regenerative medicine product (the encapsulated liver tissue, ELT) that proved capable to treat acute liver failure (ALF) in immunocompetent mice, improving survival, treating hepatic encephalopathy (HE) and accelerating liver regeneration, without the need for immunosuppression and being explanted once the recipient’s own liver regenerated. We filed 3 patents and span off a regenerative medicine company, Morphocell Technologies, which is now helping us bring the ELT to the clinic as an allogeneic therapy for ALF. The company is on schedule to file for a CTA/IND within the next 3 years. With Morphocell, we recently confirmed the feasibility, safety and proof-of-concept efficacy of implanting a clinical-scale ELT in a swine model of ALF. All data show that the ELT has a significant competitive advantage over competing approaches and is a promising first-in-class treatment for ALF. With the project proposed here, we aim at validating the safety and efficacy of the ELT for the treatment of acute-on-chronic liver failure (ACLF). As severe as ALF but developing in patients with underlying chronic liver disease, ACLF represents an unmet health need (>30,000 cases per year in North America, 50% mortality rate, >$18B global market). With the aim of extending the indication of the ELT to the treatment of ACLF, we partner with Morphocell to assess how the ELT behaves faced with ACLF’s inflammatory environment, the presence of ascites, and a reduced liver regeneration potential. We will assess the effect of inflammatory cytokines on the ELT and measure its functions in vivo at longer term. We will then evaluate its efficacy on survival, HE and liver regeneration in mouse and rat models of ACLF. The safety of the implant and the impact of the inflammatory environment and portal hypertension on rejection and the ELT survival and functions will be studied, together with the feasibility of explanting it once the decompensation resolved. Overall, this project will allow generating strong data in support of an expansion of the indication of the ELT to ACLF in view of upcoming discussions with regulators for approaching clinical phases.
1 avril 2023
31 janvier 2025
2023
Fabio Rossi (P)
University of British Columbia
Subventions de soutien aux partenariats biotechnologiques
Rossi
Chercheur principal
Fabio Rossi, Bettina Willie, Frank Rauch
194 121
Bone targeted EP4 agonists as therapeutics for muscular dystrophy
Maladie musculaire, maladies musculaires
Duchenne Muscular Dystrophy, bone regeneration, muscle regeneration, PGE2,
Duchenne Muscular Dystrophy (DMD) patients undergo rapid loss of muscle mass, leading to impaired motility. Associated and possibly secondary to this drop in muscle strength and to the current steroid-based disease management, most patients develop significant bone loss, especially in vertebrae, eventually leading to spontaneous painful fractures that have a severe impact on their quality of life. We found that bone loss is also present in a new rat model of DMD. Working with Mesentech, a Canadian biotech working on bringing bone anabolic compounds to the clinic, we generated preliminary results showing that treatment of these rats with a compound that is targeted to the bone surface, and releases an active EP4 prostaglandin receptor agonist at this location, leads to strong new bone formation. Surprisingly, but consistent with recent report that EP4 activity is required for efficient muscle stem cell function, we also saw a significant increase in muscle mass. Here, we propose to follow up on these results, to establish 1) whether treatment with this compound leads to improvements in the function of bone (less prone to fracture) and of muscle (enhance muscle strength and endurance). 2) the cellular mechanisms underlying the observed changes, at the level of bone and muscle progenitors. The overall goal of this project is to validate the use of this compound as a management strategy for muscular dystrophy, thus expand the commercialization potential of this new drug beyond bone afflictions.
1 avril 2023
31 janvier 2025
2023
Bettina Willie (C)
Université McGill
Subventions de soutien aux partenariats biotechnologiques
Rossi
Cochercheur
Fabio Rossi, Bettina Willie, Frank Rauch
108 740
Bone targeted EP4 agonists as therapeutics for muscular dystrophy
Maladie musculaire, maladies musculaires
Duchenne Muscular Dystrophy, bone regeneration, muscle regeneration, PGE2,
Duchenne Muscular Dystrophy (DMD) patients undergo rapid loss of muscle mass, leading to impaired motility. Associated and possibly secondary to this drop in muscle strength and to the current steroid-based disease management, most patients develop significant bone loss, especially in vertebrae, eventually leading to spontaneous painful fractures that have a severe impact on their quality of life. We found that bone loss is also present in a new rat model of DMD. Working with Mesentech, a Canadian biotech working on bringing bone anabolic compounds to the clinic, we generated preliminary results showing that treatment of these rats with a compound that is targeted to the bone surface, and releases an active EP4 prostaglandin receptor agonist at this location, leads to strong new bone formation. Surprisingly, but consistent with recent report that EP4 activity is required for efficient muscle stem cell function, we also saw a significant increase in muscle mass. Here, we propose to follow up on these results, to establish 1) whether treatment with this compound leads to improvements in the function of bone (less prone to fracture) and of muscle (enhance muscle strength and endurance). 2) the cellular mechanisms underlying the observed changes, at the level of bone and muscle progenitors. The overall goal of this project is to validate the use of this compound as a management strategy for muscular dystrophy, thus expand the commercialization potential of this new drug beyond bone afflictions.
1 avril 2023
31 janvier 2025
2023
Frank Rauch (C)
Université McGill
Subventions de soutien aux partenariats biotechnologiques
Rossi
Cochercheur
Fabio Rossi, Bettina Willie, Frank Rauch
96 960
Bone targeted EP4 agonists as therapeutics for muscular dystrophy
Maladie musculaire, maladies musculaires
Duchenne Muscular Dystrophy, bone regeneration, muscle regeneration, PGE2,
Duchenne Muscular Dystrophy (DMD) patients undergo rapid loss of muscle mass, leading to impaired motility. Associated and possibly secondary to this drop in muscle strength and to the current steroid-based disease management, most patients develop significant bone loss, especially in vertebrae, eventually leading to spontaneous painful fractures that have a severe impact on their quality of life. We found that bone loss is also present in a new rat model of DMD. Working with Mesentech, a Canadian biotech working on bringing bone anabolic compounds to the clinic, we generated preliminary results showing that treatment of these rats with a compound that is targeted to the bone surface, and releases an active EP4 prostaglandin receptor agonist at this location, leads to strong new bone formation. Surprisingly, but consistent with recent report that EP4 activity is required for efficient muscle stem cell function, we also saw a significant increase in muscle mass. Here, we propose to follow up on these results, to establish 1) whether treatment with this compound leads to improvements in the function of bone (less prone to fracture) and of muscle (enhance muscle strength and endurance). 2) the cellular mechanisms underlying the observed changes, at the level of bone and muscle progenitors. The overall goal of this project is to validate the use of this compound as a management strategy for muscular dystrophy, thus expand the commercialization potential of this new drug beyond bone afflictions.
1 avril 2023
31 janvier 2025
2023
Jason Guertin (P)
Université Laval
Subventions aux projets à fort impact : filière des QEJS
Guertin
Chercheur principal
Jason Guertin
200 000
Supporting the use of early economic evaluations within the regenerative medicine field
Background and Relevance Economic evaluations in health are a family of methods that examine the incremental cost and incremental effectiveness of a health technology over one or many others. They have become a pivotal component of the health technology assessment process. Recently, Canadian and international experts have proposed to expand the use of economic evaluations to help researchers working in the regenerative medicine field design and adapt their technologies to improve their cost-effectiveness profile; such work is often referred to as the early economic evaluation of a technology. Value of these early economic evaluations in the regenerative medicine field is expected to be substantial since technologies arising from this field are often costly and frequently used within small and highly heterogeneous populations. Unfortunately, uptake within the regenerative medicine field is greatly limited by research capacity in the health economic field. Research Aims The primary objective of this proposal is to facilitate the use of early economic evaluations within the regenerative medicine field. A secondary objective of this proposal is to design a series of knowledge translation tools tailored to the needs of fundamental and clinical researchers. Methods The proposal will include both empirical cost studies and economic simulations combined with various knowledge translation tools. Empirical cost studies will be based on data provided from cost studies. We will also create novel simulation models aimed at assessing the economic value of various regenerative medicine technologies. Initial work will focus on supporting the early economic evaluation of the self-assembled skin substitute (SASS), currently being developed at the LOEX in Quebec City. Core Expertise Our study team is composed of various experts in Health Economics, Plastic Surgery, and Tissue Engineering. In addition, a burn survivor has agreed to join our team as a patient partner. Expected Outcomes We will provide novel cost data relevant to the early economic evaluation of the SASS technology. In addition, we plan to train HQP in health economics with specific expertise in the regenerative medicine clinical area. Finally, we plan to design various knowledge mobilization tools facilitating future economic analyses by others.
1 avril 2023
31 janvier 2025
2023
Manoj Lalu (P)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions aux projets à fort impact : filière des QEJS
Lalu
Chercheur principal
Manoj Lalu, Jonathan Kimmelman, Dean Fergusson, Agnes Grudniewicz
101 142
Developing guidance to translate promising cell therapies to early phase clinical trials
Participation des patients à la recherche, engagement des patients
Testing new cell therapies in humans is very slow (taking up to 10-20 years) and expensive (hundreds of millions of dollars). Thus, most cell therapies are first tested in animals as this can be done efficiently, for less money, and allow us to test many more treatments than possible in humans alone. However, very few cell therapies that seem effective in animals end up working well in humans. It is surprising then that widely adopted guidance does not exist to define critical elements that should be considered when contemplating translating a therapy from the lab to an early phase clinical trial. For instance, how do we judge if a treatment that works in animals has a good chance of also working in humans? In fact, we don’t even know what types of evidence clinical trialists consider when they decide whether to initiate an early phase clinical trial. Elucidating these details might help us improve both the way we test advanced cell therapies in the lab and how we choose promising candidates to enter clinical trials. Here, we propose to fill this knowledge gap by defining essential features that should be considered to optimize translation of promising cell therapies. We are currently conducting scoping reviews to comprehensively identify and map current preclinical and clinical understanding of evidence criteria for advancing promising cell therapies to clinical evaluation, from both a regulatory (Review 1) and clinical investigator (Review 2) perspective. In order to gain a deeper understanding of scoping review findings we will generate; we will next conduct an interview study of key stakeholders identified by these studies. Using results of the reviews and interviews, we will then form a diverse working group of international stakeholders to synthesize and draft guidance on critical elements that should be evaluated when considering translation of a promising cell therapy. This guidance will be refined through a Delphi survey process. We will promote uptake of developed guidance through educational resources and integrated knowledge translation efforts with key stakeholders, including Stem Cell Network investigators. Guiding rigorous translation of cell therapies may increase evidence quality for therapies under development. This may enable better selection of cell therapies to advance to clinical trials.
1 avril 2023
31 janvier 2025
2023
Jonathan Kimmelman (C)
McGill University
Subventions aux projets à fort impact : filière des QEJS
Lalu
Cochercheur
Manoj Lalu, Jonathan Kimmelman, Dean Fergusson, Agnes Grudniewicz
15 000
Developing guidance to translate promising cell therapies to early phase clinical trials
Participation des patients à la recherche, engagement des patients
Testing new cell therapies in humans is very slow (taking up to 10-20 years) and expensive (hundreds of millions of dollars). Thus, most cell therapies are first tested in animals as this can be done efficiently, for less money, and allow us to test many more treatments than possible in humans alone. However, very few cell therapies that seem effective in animals end up working well in humans. It is surprising then that widely adopted guidance does not exist to define critical elements that should be considered when contemplating translating a therapy from the lab to an early phase clinical trial. For instance, how do we judge if a treatment that works in animals has a good chance of also working in humans? In fact, we don’t even know what types of evidence clinical trialists consider when they decide whether to initiate an early phase clinical trial. Elucidating these details might help us improve both the way we test advanced cell therapies in the lab and how we choose promising candidates to enter clinical trials. Here, we propose to fill this knowledge gap by defining essential features that should be considered to optimize translation of promising cell therapies. We are currently conducting scoping reviews to comprehensively identify and map current preclinical and clinical understanding of evidence criteria for advancing promising cell therapies to clinical evaluation, from both a regulatory (Review 1) and clinical investigator (Review 2) perspective. In order to gain a deeper understanding of scoping review findings we will generate; we will next conduct an interview study of key stakeholders identified by these studies. Using results of the reviews and interviews, we will then form a diverse working group of international stakeholders to synthesize and draft guidance on critical elements that should be evaluated when considering translation of a promising cell therapy. This guidance will be refined through a Delphi survey process. We will promote uptake of developed guidance through educational resources and integrated knowledge translation efforts with key stakeholders, including Stem Cell Network investigators. Guiding rigorous translation of cell therapies may increase evidence quality for therapies under development. This may enable better selection of cell therapies to advance to clinical trials.
1 avril 2023
31 janvier 2025
2023
Dean Fergusson (C)
L'Institut de recherche de l'Hôpital d'Ottawa
Subventions aux projets à fort impact : filière des QEJS
Lalu
Cochercheur
Manoj Lalu, Jonathan Kimmelman, Dean Fergusson, Agnes Grudniewicz
53 859
Developing guidance to translate promising cell therapies to early phase clinical trials
Participation des patients à la recherche, engagement des patients
Testing new cell therapies in humans is very slow (taking up to 10-20 years) and expensive (hundreds of millions of dollars). Thus, most cell therapies are first tested in animals as this can be done efficiently, for less money, and allow us to test many more treatments than possible in humans alone. However, very few cell therapies that seem effective in animals end up working well in humans. It is surprising then that widely adopted guidance does not exist to define critical elements that should be considered when contemplating translating a therapy from the lab to an early phase clinical trial. For instance, how do we judge if a treatment that works in animals has a good chance of also working in humans? In fact, we don’t even know what types of evidence clinical trialists consider when they decide whether to initiate an early phase clinical trial. Elucidating these details might help us improve both the way we test advanced cell therapies in the lab and how we choose promising candidates to enter clinical trials. Here, we propose to fill this knowledge gap by defining essential features that should be considered to optimize translation of promising cell therapies. We are currently conducting scoping reviews to comprehensively identify and map current preclinical and clinical understanding of evidence criteria for advancing promising cell therapies to clinical evaluation, from both a regulatory (Review 1) and clinical investigator (Review 2) perspective. In order to gain a deeper understanding of scoping review findings we will generate; we will next conduct an interview study of key stakeholders identified by these studies. Using results of the reviews and interviews, we will then form a diverse working group of international stakeholders to synthesize and draft guidance on critical elements that should be evaluated when considering translation of a promising cell therapy. This guidance will be refined through a Delphi survey process. We will promote uptake of developed guidance through educational resources and integrated knowledge translation efforts with key stakeholders, including Stem Cell Network investigators. Guiding rigorous translation of cell therapies may increase evidence quality for therapies under development. This may enable better selection of cell therapies to advance to clinical trials.
1 avril 2023
31 janvier 2025
2023
Agnes Grudniewicz (C)
Université d’Ottawa
Subventions aux projets à fort impact : filière des QEJS
Lalu
Cochercheur
Manoj Lalu, Jonathan Kimmelman, Dean Fergusson, Agnes Grudniewicz
30 000
Developing guidance to translate promising cell therapies to early phase clinical trials
Participation des patients à la recherche, engagement des patients
Testing new cell therapies in humans is very slow (taking up to 10-20 years) and expensive (hundreds of millions of dollars). Thus, most cell therapies are first tested in animals as this can be done efficiently, for less money, and allow us to test many more treatments than possible in humans alone. However, very few cell therapies that seem effective in animals end up working well in humans. It is surprising then that widely adopted guidance does not exist to define critical elements that should be considered when contemplating translating a therapy from the lab to an early phase clinical trial. For instance, how do we judge if a treatment that works in animals has a good chance of also working in humans? In fact, we don’t even know what types of evidence clinical trialists consider when they decide whether to initiate an early phase clinical trial. Elucidating these details might help us improve both the way we test advanced cell therapies in the lab and how we choose promising candidates to enter clinical trials. Here, we propose to fill this knowledge gap by defining essential features that should be considered to optimize translation of promising cell therapies. We are currently conducting scoping reviews to comprehensively identify and map current preclinical and clinical understanding of evidence criteria for advancing promising cell therapies to clinical evaluation, from both a regulatory (Review 1) and clinical investigator (Review 2) perspective. In order to gain a deeper understanding of scoping review findings we will generate; we will next conduct an interview study of key stakeholders identified by these studies. Using results of the reviews and interviews, we will then form a diverse working group of international stakeholders to synthesize and draft guidance on critical elements that should be evaluated when considering translation of a promising cell therapy. This guidance will be refined through a Delphi survey process. We will promote uptake of developed guidance through educational resources and integrated knowledge translation efforts with key stakeholders, including Stem Cell Network investigators. Guiding rigorous translation of cell therapies may increase evidence quality for therapies under development. This may enable better selection of cell therapies to advance to clinical trials.
1 avril 2023
31 janvier 2025
2023
Colin Crist (P)
Sir Mortimer B. Davis-Jewish General Hospital
Subventions de soutien aux projets à fort impact
Crist
Chercheur principal
Colin Crist
250 000
Shining light on muscle regeneration: MuSC mediated delivery of optogenetic contractile properties to skeletal muscle
Maladie musculaire, maladies musculaires
Muscle stem cell, ex vivo expansion, genetic manipulation, channelrhodopsin, optogenetics
Although skeletal muscle has a remarkable muscle stem cell (MuSC) dependent capacity for regeneration, it is subject to several diseases, including a large family of muscular dystrophies, as well as muscle wasting associated with cancer and aging. Muscle atrophy and paralysis is a
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