Results of the SCN 2022-2025 Research Funding Competition

Early Career Researcher Jump Start Awards Program

Title: Targeting muscle stem cell dysfunction

PI: Natasha Chang
Co-I: Nicolas Dumont, Bénédicte Chazaud, Pura Muñoz-Canoves

Abstract:
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 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).

Impact Awards Program

Title: Combining tissue-engineered skin with ex vivo gene therapy correction for developing a treatment for epidermolysis bullosa

PI: Lucie Germain (Université Laval)
Co-I: Manuel Caruso, Elena Pope, Bartha Knoppers

Abstract:
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. Patients experience pain and a poor quality of life. The LOEX (CHU de Québec-Université Laval), one of the leading organ reconstruction laboratories in the world, developed the autologous self-assembled skin substitute (SASS) therapy for burn patients and has initiated research studies to find a cure 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 self-assembled skin substitutes 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 Submission of a Clinical Trial Application to Health Canada; and #3 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 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 impact 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.

Clinical Trial Awards Program

Title: Tissue engineering to treat Canadian burn patients: the Self-Assembled Skin Substitutes (SASS)

PI: Véronique Moulin (Université Laval)
Co-I: Lucie Germain, Bartha Knoppers

Abstract:
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 3 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 three 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 and Quebec Fireman Foundation. Upon Health Canada approval, we will be the first in Canada to routinely and successfully treat patients with autologous reconstructed skin.

Translation & Society Teams Award

Title: Responsible Pathways for Pediatric Cell Therapies

PI: Vardit Ravitsky (UdeM)
Co-I: Ma’n Zawati, Jonathan Kimmelman

Abstract:
Recent advances surrounding regenerative medicine technologies have led to cell and gene therapies making their way into clinical trials, with new preventive and therapeutic options. Such clinical translation, however, requires addressing socio-ethical, legal, and regulatory issues, as well as public perception and trust. Gaps currently exist in the regulation and education of entities involved in the approval and oversight of clinical trials using cell and gene therapies. This is particularly notable in the pediatric context, as children are often the focus of early cell and gene therapies meant to prevent, delay, or treat early-onset diseases.

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. Children are recognized as a vulnerable population, requiring not only legal protections to safeguard them from harm, but also their inclusion in clinical trials for their potential benefit. We will address their possible recognition and inclusion as stakeholders, based on their level of maturity, the role and limits of parental authority, both clinicians’ and researchers’ professional duties, and explore the promotion of research/regulatory systems that foster children’s best interests. To achieve this, we will address:

• Responsibilities: enhanced conceptual clarity regarding the legal roles and responsibilities of clinicians/researchers and of parents/families.
• Rights of children: analysis of the ambit and implications of children’s rights, best interests, and capacity to make autonomous decisions regarding involvement in clinical trials.
• Research trajectories: development of tools to assist in the assessment of safety, efficacy, and the balance of risk and potential benefit, when moving to first-in-human clinical trials.
• Resources: development of training and educational resources for regulators, researchers, and REBs, to facilitate approvals and clinical translation.

To promote translation in real-time, we will use 2 case studies:

• Jacques Tremblay’s research on Duchenne Muscular Dystrophy (DMD) at Laval University.
• Isaac Odame’s (University of Toronto) research on Sickle Cell disease at SickKids and Dr. Julie Makani’s (Muhimbili University) research on sickle cell disease at Muhimbili National Hospital.