For 30 years, we have known that research is the only way to find a cure and improve care for those living with Duchenne muscular dystrophy.
Since 1995, Defeat Duchenne Canada has believed in developing strong partnerships with academics and clinicians to fund the most promising research. While science is the method behind our mission, there would be no progress without people like you.
Donations from our community, and the stories behind them, are the only reasons we have been able to fund the life-changing research milestones you will learn more about below.
To date, Defeat Duchenne Canada has funded over $20.3 million across 80+ research projects around the world.
Funded Research Projects
Funded Projects in 2025
Dr. James Dowling
University of Pennsylvania – Pennsylvania, USA
“Non Viral Gene Therapy for Duchenne Muscular Dystrophy”
About Dr. James Dowling
Dr. James Dowling is a Professor of Neurology and Genetics, and a clinician scientist Neurologist with specialization in neuromuscular medicine.
His clinical work is focused on neuromuscular and neurogenetic disorders, and he directs the Penn Neurogenetics Therapy Center. His research is focused on defining pathomechanisms and developing therapies for childhood muscle diseases. This encompasses gene discovery, pre-clinical model development and characterization, and therapy identification and translation, and additionally observational and interventional clinical studies.
He has led or co-led several multi investigator initiatives related to both pre-clinical and clinical research, and has successfully administered several of these projects. Dr. Dowling has advised on numerous studies related to the use of zebrafish, mice, and cells as models to study neuromuscular disorders, and also has supervised several PhD students, postdoctoral fellows, and clinician scientist trainees.
Research Overview
There is a continued unmet need to develop new treatments for Duchenne Muscular Dystrophy. Viral vector delivered gene therapy of micro dystrophin has potential, and is now FDA approved in the United States. However, there are significant concerns about its safety, and it appears to be of limited effectiveness. One reason for its lack of strong benefit is the fact that this gene therapy provides only a miniaturized version of dystrophin that is 1/3 the size of the full length protein. Identifying an alternative gene therapy strategy that overcomes the limitations related to safety and dystrophin size would therefore be of great potential benefit for DMD. mRNA therapy, given using lipid nanoparticles (i.e. mRNA-LNP), is a safe potential option that enables delivery of a full length version of the dystrophin mRNA, which can be made into a fully functional dystrophin protein. mRNA-LNPs were the basis of the COVID vaccine, and now have been proven effective for rare genetic metabolic diseases, and have shown great benefit and safety. The also present the ability to be made at scale at a fraction of the cost of viral gene therapy.
A key barrier for mRNA-LNP therapy for muscle diseases is the challenge of delivering LNPs to muscle after ‘systemic’ (intravenous) administration. In this proposal, we will overcome this barrier, and develop and delivery a safe and effective full length dystrophin mRNA to all of the muscles in the body. For this study, we will execute on this plan in a compressed time period (2 years) using the mouse model of the disease, recognizing its limitations as a predictive model but emphasizing its strengths for enabling the testing of 100s of mRNA-LNP combinations in a short time period. The goal is to then rapidly translate our discovery to the clinic, as we have done for other mRNA therapies. Successful development of this potentially transformative therapeutic approach is aided by the experience of the two principal investigators, one (Weissman) who is a world leading pioneer of mRNA-LNP, and the other (Dowling) who is a recognized international expert in therapy development for childhood muscle diseases.
Dr. Laura McAdam
Holland Bloorview Kids Rehabilitation Hospital – Toronto, Canada
“Youth Helping Youth: Dissemination of a user-informed bullying resource for youth with Duchenne Muscular Dystrophy across Canada”
About Dr. Laura McAdam
Dr. Laura McAdam’s research focuses on three main areas: enhancing care for children with neuromuscular conditions, advancing rehabilitation for children with rare diseases, and understanding the broader impact of rare conditions. To achieve these goals, she leads investigator driven research projects focusing on rehabilitation and the impact of bullying. She collaborates nationally and internationally in studies investigating natural history, chronic corticosteroid treatment’s effects on bone health, and respiratory interventions.
Through her research, she seeks to bridge knowledge gaps, improve patient care, and address the multi-faceted challenges faced by individuals with rare diseases and their caregivers.
Research Overview
Despite increasing awareness and anti-bullying strategies, bullying is a global problem that impacts children and adolescents. Children with a disability are 1.7 times more likely to be bullied than children without a disability. Despite research on bullying amongst children and youth with disabilities, there was a gap in research about the bullying experiences of children and youth with progressive muscle weakness such as Duchenne Muscular Dystrophy (DMD).
The project team conducted a research study to explore the frequency and experiences of bullying of youth with neuromuscular diseases like DMD. Findings resulted in a knowledge mobilization product, the Bullying Report, which is a 10-page document containing tangible strategies and recommendations for coping with bullying and bullying prevention for key stakeholders (youth, families, schools, clinicians) informed by youth participants.
Now it is time to disseminate the Bullying Report widely to the DMD community across Canada. The objectives of the proposed study include: 1) prepare the Bullying Report for dissemination; 2) disseminate the Bullying Report; and, 3) evaluate its reach and impact. We will share the Bullying Report in accessible formats for use across Canada and evaluate it using the RE-AIM framework. Implementation of the Bullying Report may enable youth with DMD and their families to confidently take pro-active action to minimize bullying and build confidence in navigating possible bullying events. Anticipate outcomes include a positive impact on quality of life.
Dr. Christopher Spurney
Children’s National Hospital – Washington, USA
“Does vamorolone delay cardiac disease and rescue puberty in DMD?”
About Dr. Christopher Spurney
Dr. Spurney has studied cardiac disease related to muscular dystrophies for over 20 years. His early work focused on preclinical drug testing in dystrophin deficient animal models. This work led to the paper demonstrating the mineralocorticoid receptor antagonism properties of vamorolone. His current research is focused on clinical imaging biomarkers of cardiac disease in DMD, including cardiac magnetic resonance imaging. He published studies using MRI derived native T1 myocardial characterization and myocardial strain. This proposal incorporates all these strengths. He has worked closely with members of the study team in DMD research to ensure success of the proposal.
Research Overview
Vamorolone is a novel steroidal anti-inflammatory that has been developed for DMD. In a double-blind, placebo- and prednisone-controlled trial of vamorolone at two doses (2.0 and 6.0 mg/kg/day), vamorolone showed strong evidence of efficacy vs. placebo, and loss of key side effects of corticosteroids (no stunting of growth, no deleterious changes in bone biomarkers, less disturbance of behavior). In addition to the demonstrated benefits to skeletal muscle, vamorolone has a potential benefit to heart health in DMD that is distinct from corticosteroids (prednisone, deflazacort). Vamorolone is known to have activity similar to two cardiac drugs used in later-stage DMD (eplerenone, spironolactone), whereas corticosteroids lack this activity. Thus, we hypothesize that long-term treatment of DMD boys with vamorolone may delay or prevent the onset of cardiac disease in DMD.
While DMD boys show muscle weakness at a relatively young age (~4-5 years or earlier), the heart disease becomes clinically significant later (teens). Despite its later onset, DMD heart disease is often the cause of death. The primary objective of this study is to determine if early and long-term treatment of DMD boys with vamorolone (4 to 7 years old at start of treatment) delays onset of later cardiac disease (cardiomyopathy).
Funded Projects in 2024
Dr. Francesco Muntoni
Dubowitz Neuromuscular Centre – London, UK
“AAV gene therapy for DMD related brain dystrophin deficiency”
About Dr. Francesco Muntoni
Francesco Muntoni is a Professor of Paediatric Neurology and the Director of the Dubowitz Neuromuscular Centre, at the UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK.
In the Institute and the hospital, he led the Novel Therapies Programme of the Biomedical Research Centre and between 2008 and 2022 and also the Developmental Neuroscience Programme between 2008 and 2018.
Since 2022 Muntoni is also director of the Genetic Therapy Accelerator Centre, a new gene therapy translational research partnership, based at Queen Square Institute of Neurology and in close collaboration with the UCL Great Ormond Street Institute of Child Health. This cross-faculty collaboration within UCL is driving forward an exciting evolving RNA and AAV gene therapy area with direct therapeutic benefits for patients with disabling neurological conditions.
Muntoni has an interest in pathogenesis, deep phenotyping, gene identification for rare neuromuscular conditions and translational research in Duchenne muscular dystrophy, spinal muscular atrophy and congenital myopathies. He is involved in several natural history studies and clinical trials. His research funded by the Department of Health, MRC and the European commission lead to the development and early clinical trials of 2 morpholino antisense oligonucleotides, now approved by FDA, that induce partial correction of the processing defect of the DMD gene in boys with Duchenne muscular dystrophy.
Muntoni is the chief investigator of the European consortium BIND (Brain Involvement in Dystrophinopathies, https://bindproject.eu/) focusing on the brain comorbidities observed in a proportion of patients with Duchenne muscular dystrophy, and exploring both their biological basis, clinical assessment tools and preclinical translational research.
In the last few years he obtained several international awards, including the 2022 Ottorino Rossi Award, the World Duchenne Organisation 2022 Leadership Awards, the 2023 European Paediatric Neurology Society Jean Aicardi Award and the 2024 Muscular Dystrophy UK President Award.
Research Overview
Duchenne muscular dystrophy (DMD) is a rare inherited disorder affecting boys, causing progressive muscle degeneration. Most of the studies and therapeutic approaches have focused on slowing down muscle weakness, to delay the age at which walking ability is lost, improve respiratory function and survival.
An underappreciated problem many children face is the effects the disease has on the brain. Half of affected boys having learning disability, or behavioural disorders such as attention deficit hyperactivity disorder and autism. This is related to the lack of dystrophin in the brain, the same component that is defective in muscle. There are no current treatments addressing the brain involvement in DMD boys. This unmet need affects families immensely and is associated with poorer muscle function and survival.
We and others have evaluated a genetic therapy approach called antisense oligonucleotide (ASO) to treat the brain of dystrophic mice that resulted in behavioural improvement. This is very exciting as it suggests re-expression of brain dystrophin could improve behavioural outcomes. However more efficient and practical ways to deliver these therapies to the brain are needed. In this research proposal we will develop novel brain-directed DMD genetic therapies, and assess their efficacy in mouse models.
We will use AAV gene therapy (Adeno-associated virus) to see if this can treat the brain in DMD mouse models. This is based on the recent encouraging FDA approval of AAV gene therapy for DMD muscle disease called Elevidys and we will see if these types of gene therapies can also treat the dystrophin loss in the brain. We will have a new DMD mouse model produced that means we control when dystrophin is lost to see how dystrophin affects brain development. We will evaluate mice with dystrophin loss during pregnancy, as new born and adult mice and assess the behavioural differences. We know that DMD mouse models have abnormal behaviours related to stress, anxiety and learning. We will look for these in our mouse model and treat these mice with gene therapy to see if these behaviours are treated with AAV gene therapy.
Dr. Alain Stintzi
School of Pharmaceutical Sciences, Faculty of Medicine, University of Ottawa
“Unlocking Therapeutic Potential: Exploring Gut Microbiota Functionality for Novel and Cost-effective DMD Treatment”
About Dr. Alain Stintzi
Dr. Stintzi is a professor and the Interim Director of the School of Pharmaceutical Sciences at the Faculty of Medicine, University of Ottawa.
He earned his Ph.D. in Molecular and Cellular Biology from Louis Pasteur University, France, in 1997. Following this, he was a postdoctoral fellow in the Department of Chemistry at the University of California, Berkeley, where he studied iron transport by siderophores. In 2000, he was appointed Assistant Professor in the Department of Veterinary Pathobiology at Oklahoma State University. In July 2005, he joined the University of Ottawa as an Associate Professor in the Department of Biochemistry, Microbiology, and Immunology and became a member of the Ottawa Institute of Systems Biology. He was promoted to Professor in 2012 and served as Vice-Dean of Graduate and Postdoctoral Studies from September 2013 to April 2024.
Dr. Stintzi possesses unique cross-disciplinary experience, and his current research combines techniques from various scientific fields, including gut microbiology, genetics, functional genomics, medicine, chemistry, biochemistry, and bioinformatics, to study the role of the gut microbiome in human diseases.
Research Overview
Duchenne Muscular Dystrophy (DMD) is a devastating genetic disorder characterized by profound muscle degeneration, with limited effective treatment options. In addition, patients with DMD often suffer from gastrointestinal and cardiac complications, mainly due to their increasing loss of muscle strength. These changes in muscle occurring across the body will likely alter the gut microbiotas of patients with DMD, but there has been limited research into the gut microbiota of patients with DMD and we currently do not fully understand how microbiota alterations impact muscle health. However, recent findings from mouse models have indicated a potential link between DMD pathogenesis and their gut microbiotas. They also suggest that the gut microbes in DMD mouse models can impact their overall muscle health.
Our study aims to explore this connection by investigating the function of gut microbiota in DMD mice and assessing whether increasing the levels of beneficial bacteria can improve muscle strength. Utilizing advanced screening techniques, we will identify dietary fibers that promote the growth of these beneficial bacteria and determine whether these dietary fibers could improve muscle health and other symptoms of DMD in these mice.
If successful, this approach offers a promising avenue for developing novel and cost-effective dietary-based therapeutic interventions for DMD, with the goal of halting or slowing disease progression and reducing their gastrointestinal and cardiac complications.
Moreover, our research seeks to deepen our understanding of the intricate relationship between gut bacteria and muscle function, shedding light on exactly how DMD disease progresses over time. This investigation thus holds the potential to pave the way for innovative treatments targeting gut microbiota to improve muscle health. In particular, our approach would target an under appreciated aspect of DMD and represents a completely new, non-pharmaceutical avenue for treating patients with DMD that could be cheaply, easily and rapidly employed alongside current treatments.
Ultimately, our therapeutic intervention could mitigate symptoms associated with disease progression, including limitations in mobility, respiratory complications, and cardiac issues, thereby enhancing patient quality of life and extending the lifespan of individuals affected by DMD.
Dr. Reshma Amin
The Hospital for Sick Children (SickKids), Toronto, ON
“Real World Evidence for Canadian Neuromuscular Disease: Establishing a Framework for National Integration of Patient Report”
About Dr. Reshma Amin
Dr. Reshma Amin is a Pediatric Respirologist and the Director of Sleep Medicine and Long-Term Ventilation at the Hospital for Sick Children. She is a Clinician-Investigator and
Dr. Amin’s research program which includes multi-center randomized controlled trials and observational studies—focuses on characterizing the care burden experienced by children who have neuromuscular disease as well as those that use home mechanical ventilation. She is focused on evaluating innovative care delivery models. Her work aims to improve patient and family health-related quality of life, reduce preventable healthcare utilization, and enhance patient safety. In addition, her research integrates patient-reported outcomes and real-world evidence to inform national policy and healthcare strategies. She also serves as Director of the Canadian Home Mechanical Ventilation Research Network.
Research Overview
Our research aims to create a more complete picture of health by combining different types of data- including registry data, patient reported outcomes, clinical data, healthcare use including hospital admissions and Emergency Room visits and costs-into one system. This will allow for a true picture of what life is like to live with a neuromuscular disease in Canada.
There are two parts to this project. In part 1 we will link data from the Canadian Neuromuscular Disease Registry with health administrative databases from 5 provinces across Canada. This will help us understand how individuals with Spinal Muscular Atrophy and Duchenne Muscular Dystrophy use the healthcare system. We will learn about Emergency Room visits, hospital admissions, visits to specialists as well as clinical testing. We are also hoping to look at the effect of disease modifying therapies on healthcare use. In part 2, we will set up 4 cohorts of individuals with neuromuscular disease that we will follow forward for 2 years. Individuals will have a diagnosis of Spinal Muscular Atrophy, Duchenne Muscular Dystrophy, Spinal Bulbar Muscular Atrophy and Oculopharyngeal Muscular Dystrophy. We will collect clinical information, patient-reported outcomes, and out-of-pocket costs. The 4 cohorts will then be linked nationally to health administrative databases at Statistics Canada to obtain data on healthcare use. Through this linkage with Statistics Canada, we will also be able to better understand differences in access in access to care across Canada, such as those related to geography or socioeconomic factors.
Because neuromuscular diseases are complex and require coordinated care, this work will serve as a model for improving data and care for Duchenne Muscular Dystrophy and other rare diseases in Canada. It will also support improvements in how rare diseases are tracked in Canada’s health data systems.
This work would not be possible without our funders: Canadian Institute of Health Research, Defeat Duchenne Canada, Cure SMA Canada and Muscular Dystrophy Canada.
Funded Projects in 2023
Dr. Leanne Ward
Children’s Hospital of Eastern Ontario (CHEO) – Ottawa, ON
Two-Year Fellowship Grant in Partnership with Parent Project Muscular Dystrophy (PPMD)
About Dr. Leanne Ward
Full Professor, Medical Director of the CHEO Bone Health Clinic, Scientific Director of the Ottawa Pediatric Bone Health Research Group
Research Chair in Pediatric Bone Health, University of Ottawa
Pediatric Endocrinologist, Division of Endocrinology and Metabolism, CHEO
Dr. Ward’s research program is dedicated to the study of bone development and the diagnosis and treatment of bone disorders in children, including osteoporosis and rickets. She has been the principal investigator of the “STOPP” research program (STeroid-induced Osteoporosis in the Pediatric Population) since 2003, a pan-Canadian project funded by the Canadian Institutes of Health Research to evaluate the effect of glucocorticoids on bone health in children with chronic illnesses. This multi-centre longitudinal research program has unveiled the natural history of osteoporotic fractures in children with steroid-treated disorders, including the clinical hallmark of this disorder in children, vertebral fractures. The results of the STOPP Consortium’s work under Dr. Ward’s leadership have played a major role in informing the approach to diagnosing steroid-induced osteoporosis in children, monitoring those at risk, and identifying children in need of osteoporosis prevention and intervention.
Dr. Ward is actively involved in and leads a number of clinical trials for children with osteogenesis imperfecta, rickets (including X-linked hypophosphatemia), and chronic illness osteoporosis, including Duchenne muscular dystrophy (DMD). She has served as an endocrinology and bone health advisor to various international organizations, including the Centres for Disease Control Clinical Care Guidelines for DMD, the International Late Effects of Childhood Cancer Guideline Harmonization Group, the International Society for Clinical Densitometry and the International Conference on Children’s Bone Health. She is the founder and chair of the Canadian Pediatric Bone Health Working Group and a frequently invited speaker at international bone and endocrinology conferences.
Dr. Ward has published over 130 original peer-reviewed manuscripts, book chapters and reports and has received awards for her work in pediatric bone health, including a Canadian Child Health Clinician Scientist Career Development Award, a Canadian Institutes for Health Research New Investigator Award, a Canadian Child Health Clinician Scientist Career Enhancement Award, and two, five-year Research Chairs in Pediatric Bone Health (University of Ottawa, 2010 and 2015).
In 2019, Dr. Ward was named a Fellow of the American Society of Bone and Mineral Research, an award in recognition of significant contributions to bone and mineral science.
Research Overview
Defeat Duchenne Canada, Canada’s leading charity fighting to defeat Duchenne, and Parent Project Muscular Dystrophy (PPMD), a US nonprofit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), have announced a collaborative research award of $300,000 (USD) in support of two Clinical Fellowships in Duchenne Endocrinology and Bone Fragility.
The three-year award will sponsor the extended fellowship of Dr. Kim Phung, as well as new fellow Dr. Rana Halloun, under the guidance of Dr. Leanne Ward, Professor of Pediatrics and Research Chair in Pediatric Bone Disorders at the University of Ottawa.
Dr. Ronald Cohn
The Hospital for Sick Children (SickKids) – Toronto, ON
“Combinatorial CRISPR/Cas9-mediated duplication removal and glucocorticoid treatment in a humanized mouse model of a DMD duplication”
About Dr. Ronald Cohn
Dr. Ronald Cohn has served as President and CEO of the Hospital for Sick Children (SickKids) in Toronto, Canada, since May 1, 2019. Dr. Cohn joined SickKids in September 2012 as the Chief of the Division of Clinical and Metabolic Genetics, Co-Director of the Centre for Genetic Medicine, and Senior Scientist at the SickKids Research Institute. He became the Inaugural Women’s Auxiliary Chair in Clinical and Metabolic Genetics in April of 2013 and joined the Department of Molecular Genetics at the University of Toronto. In 2016, he was appointed Chief of Paediatrics at SickKids and Chair of Paediatrics at The University of Toronto.
Dr. Cohn received his medical degree from the University of Essen, Germany. After his postdoctoral fellowship at the Howard Hughes Medical Institute in the laboratory of Dr. Kevin Campbell, he moved to Baltimore, where he was the first combined resident in pediatrics and genetics at Johns Hopkins University. He subsequently joined the faculty of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, where he became the director of the world’s first multidisciplinary centre for Hypotonia, which has earned national and international recognition.
Dr. Cohn was also the director of the medical genetics residency program at Johns Hopkins. He has received numerous awards, including the David M. Kamsler Award for outstanding compassionate and expert care of pediatric patients in 2004, the First Annual Harvard-Partners Center for Genetics and Genomics Award in Medical in 2006, and the NIH Young Innovator Award in 2008.
Over the last few years, Dr. Cohn has developed an interest in applying the concept of Precision Child Health to the care of children. His own research focuses on implementing genome editing technologies for the treatment of neurogenetic disorders.
Research Overview
Duchenne muscular dystrophy (DMD) is a condition that causes muscles to weaken and deteriorate over time. Children with DMD lose their ability to walk early in life and often face life-threatening breathing and heart issues in their 20s-30s. Existing treatments only manage symptoms, not the root cause, which is due to errors in the dystrophin gene responsible for muscle strength.
There is an urgent need for better treatments that can stop or reverse DMD. Recent advances in gene editing technology offer hope for treating genetic diseases like DMD. One breakthrough is CRISPR/Cas9, a tool that can cut and edit DNA at specific locations, providing a chance to fix genetic errors.
Dr. Cohn’s research team developed a CRISPR/Cas9-based approach to fix a specific type of error called duplications in the dystrophin gene, a common cause of DMD. They successfully removed these duplications, which significantly improved DMD symptoms in mice.
Before progressing to human trials, they need to verify the treatment’s effectiveness in a mouse model with a human version of the dystrophin gene. This is necessary because CRISPR/Cas9 targets specific DNA sequences, and human and mouse sequences differ enough that a human-designed therapy wouldn’t work well in mice.
Their plan involves creating “humanized” mouse models of DMD with duplication mutations in the dystrophin gene. They’ll test the efficacy of our duplication removal strategy in these mice.
Since most DMD patients are treated with steroids to manage symptoms, they’ll also pre-treat our mice with steroids before administering the CRISPR/Cas9 duplication removal therapy. This approach helps create an experimental setup that more closely resembles real-world conditions faced by DMD patients.
By using a steroid-treated humanized DMD mouse model, their experiment aims to provide a more accurate representation of the disease. They’re optimistic that this project could be a significant step forward in developing a CRISPR/Cas9-based treatment for DMD, paving the way for the first clinical trials using gene editing technology to treat this debilitating disease.
Dr. Natasha Chang
McGill University – Montreal, QC
“Inducing stress granule formation in muscle stem cells to treat DMD”
About Dr. Natasha Chang
Dr. Natasha Chang received her Ph.D. in Biochemistry from McGill University and pursued her postdoctoral fellowship at the Ottawa Hospital Research Institute.
Dr. Chang joined McGill as an Assistant Professor in the Department of Biochemistry in 2019. Research in the Chang laboratory focuses on understanding the molecular signalling mechanisms that regulate muscle stem cell function and how these pathways are altered in the context of muscle degenerative disease and muscle cancer. The ultimate goal for Dr. Chang’s research team is to identify molecular targets to improve endogenous stem cell regenerative capacity as well as strategies to improve stem cell transplantation therapy.
Research Overview
Duchenne muscular dystrophy (DMD) is a devastating degenerative muscle disease that affects 1 in every 5,000 Canadian male births. Despite research efforts to understand the cause and progression of the disease, there still remains no effective cure for DMD.
Emerging studies have found that muscle stem cells, which are adult stem cells that reside within the muscle tissue, are affected in DMD. In DMD, they do not function the same as normal healthy muscle stem cells, and their dysfunction plays a role in disease progression as they cannot efficiently contribute to the repair or maintenance of muscle. Her research program aims to study these stem cells in DMD and to understand how they are dysfunctional. Importantly, their goal is to correct their dysfunction.
In this research project, Dr. Chang and her team are pursuing a strategy to help restore the ability of DMD muscle stem cells to help repair muscle. The findings from this work will provide a strong foundation for boosting muscle stem cells as a valid treatment strategy for patients with DMD.
Dr. Jacques Tremblay
Laval University – Quebec City, QC
“In vivo correction by CRISPR PRIME editing of mutations responsible for Duchenne Muscular Dystrophy”
About Dr. Jacques Tremblay
Jacques P. Tremblay, Ph.D., is a professor in the Department of Molecular Medicine at Laval University. He has worked on cell and gene therapies for hereditary diseases (particularly Duchenne Muscular Dystrophy) since 1987. He has worked mainly on the transplantation of myoblasts derived from a healthy donor as a treatment for Duchenne Muscular dystrophy.
In collaboration with Dr. Jean-Pierre Bouchard, he has conducted a phase I clinical trial of that treatment. He received the Best Researcher in Canada award presented by Muscular Dystrophy Canada in 2004. In 2005, the Royal College of Physicians and Surgeons of Canada and the Canadian Society for Clinical Investigation presented the Henry Friesen Award.
In 2020, in collaboration with Dr. Craig Campbell, he initiated a phase II clinical trial of myoblast transplantation; unfortunately, this trial was discontinued because of the COVID-19 pandemic.
He is currently using the Prime editing technology (derived from the CRISPR/Cas9 technology) to correct mutations responsible for various hereditary diseases, including Duchenne Muscular Dystrophy.
Research Overview
There are two main types of mutations responsible for DMD:
Type 1) deletion of one or several exons with a total number of coding nucleotides which is not a multiple of 3 and,
Type 2) the change of only a few nucleotides resulting in a stop codon.
Both mutation types result in the production of only the beginning of the dystrophin protein, which is not functional.
Prime editing permits to modify a targeted pair of nucleotides, insert or delete several nucleotide pairs. Dr. Tremblay and his team have already used a new gene modification technology called “CRISPR-Cas9 Prime editing” to correct type 1 of mutations in cells in culture. So far, they have used the Prime editing technique to correct nine different DMD point mutations. In the present grant project, they aim to increase the frequency of correction of point mutations in DMD myoblasts by using improved Prime editing agents called PEmax and epegRNA. They will also correct point mutations in four different mouse models of DMD.
They have some preliminary results on the correction of type 2 mutations in cells in culture. During the present project, they aim to use Prime editing to restore the normal reading frame of the DMD gene in myoblasts containing an exon deletion, inducing a translation frameshift. They will also correct this type of mutation in a mouse model.
They will also verify whether the correction of mutations by prime editing induces mutation of genes other than the DMD gene.
This project’s main challenge will be delivering the Prime editing technology components to most muscles and the heart, i.e., the SpCas9 nickase fused with a reverse transcriptase and an epegRNA. Dr. Tremblay and his team will investigate four delivery methods: Adeno Associated Virus (AAV), Lipid Nano Particles (LNPs), Extra-cellular Vesicles (EVs) and Virus-Like Particles (VLPs).
Dr. Yoshitsugu Aoki & Dr. Chaitra Sathyaprakash
National Center of Neurology and Psychiatry – Tokyo, Japan
“Patient iPSC-derived brain organoids as a model for cognitive phenotypes of Duchenne muscular dystrophy”
About Dr. Yoshitsugu Aoki
Yoshitsugu Aoki is a highly accomplished neurologist and researcher. He graduated from the University of Tohoku in 2001 and had a distinguished career in clinical neurology. In 2008, he became a consultant, and in 2011, he earned a PhD from Tokyo Medical and Dental University Graduate School. In 2012, he joined Prof. Matthew Wood’s laboratory at Oxford University, which focused on developing oligonucleotide treatments for neuromuscular diseases. The Royal Society of the UK recognized Dr. Aoki’s work in 2013 for Exceptional Promise.
Currently, Dr. Aoki is the head of the Department of Molecular Therapy. He is also an Adjunct Professor at several prestigious universities in Japan. Dr. Aoki’s research primarily focuses on gene therapy for neuromuscular diseases such as Duchenne muscular dystrophy. He places a strong emphasis on mRNA splicing modulation using antisense oligonucleotides. Dr. Aoki’s notable contributions to the field include the development of VILTEPSO®, an antisense oligonucleotide-based drug that underscores his dedication to advancing therapeutic options for rare diseases. As the Japan Rare Disease Consortium leader, Dr. Aoki is committed to fostering innovation and collaboration to overcome neuromuscular diseases.
About Dr. Chaitra Sathyaprakash
Dr Chaitra Sathyaprakash has been a postdoctoral research fellow at the National Center of Neurology and Psychiatry since 2021, working on setting up human 3D model brain organoids to model cognitive phenotypes of Duchenne muscular dystrophy.
Dr. Sathyaprakash has a background in Biochemistry (BSc) from Imperial College London (2013), later specializing in Neuroscience (MSc) at University College London (2014). She worked briefly as a research assistant in RNA therapeutics at the University of Oxford with Prof Matthew Wood and Dr. Yoshitsugu Aoki, analyzing human models of motor neuron disease and linked extracellular vesicle phenotypes. From 2015 to 2019, she was awarded the Barry Bastin Fellowship (Motor Neuron Disease Association) to undertake a DPhil with Prof Kevin Talbot (Nuffield Department of Clinical Neuroscience, University of Oxford), working on transcriptomic analysis of amyotrophic lateral sclerosis iPSC-motor neuron models. For a short time, she worked with Prof Tara Spires-Jones on an Alzheimer’s Disease project, assessing synaptic phenotypes of iPSC-cortical neuron models of dementia.
Throughout her academic career, Dr. Sathyaprakash has had a strong interest in furthering our knowledge of early phenotypes of neurodegenerative and neuromuscular disease, in particular, using human-derived models to improve precision medicine-driven therapeutics and increasing the potential of larger preclinical therapeutic studies in a human-specific model. Her current work in human brain organoid models of DMD aims to improve our understanding of the early synaptic changes in the brain driven by the loss of brain-specific alternatively spliced DMD isoforms, leading to early onset autism spectrum disorder and memory impairment.
Research Overview
Duchenne muscular dystrophy (DMD) is a disease that affects boys and causes muscle weakness. Additionally, around one-third of boys with DMD are diagnosed with brain-related disorders early in life, including autism and memory difficulties. However, we do not clearly understand the processes that cause them.
The DMD gene that makes muscle dystrophin also makes smaller proteins in the brain, which are lost in patients. These proteins exist at synapses, where electrical impulses are produced for normal brain function. The loss of important proteins at synapses, both before and after birth, leads to an imbalance of electrical activity, causing various disorders. Thus, we propose making 3D ‘mini-brains’ using stem cells made from urine-derived cells, kindly donated by boys with DMD.
These ‘mini-brains’ better capture human processes compared to commonly used mouse models, whose brain chemistry and structure is very different. We aim to (1) pin down the timepoint in ‘mini-brain’ growth when short dystrophins are most important and (2) understand the processes at synapses that change when shorter dystrophin proteins are lost. This ethical, human-relevant model is also suitable for testing treatments. We hope to contribute to finding treatments for both muscle weakness and brain-related disorders in DMD patients, helping them live more independent lives.
Funded Projects in 2022
Dr. Michael Rudnicki
Ottawa Hospital Research Institute – Ottawa, ON
“Systemic Delivery of Wnt7a for Treating Duchenne Muscular Dystrophy”
About Dr. Michael Rudnicki
Michael Rudnicki is a Senior Scientist and the Director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is Professor in the Department of Medicine at the University of Ottawa. Dr. Rudnicki is CEO and Scientific Director of the Canadian Stem Cell Network (SCN). Dr. Rudnicki’s achievements have been recognized by numerous honors including being named an Officer of the Order of Canada, a Fellow of the Royal Society (London), a Fellow of the Royal Society of Canada, and International Research Scholar of the Howard Hughes Medical Institute for two consecutive terms. He has been a founder in several spin-off biotechnology companies including Satellos Bioscience.
Dr. Rudnicki is an internationally recognized thought leader in molecular genetics and regenerative medicine whose research has transformed our understanding of muscle development and regeneration and has fueled the development of novel stem cell-based approaches to treat muscular dystrophy. His work is consistently published in top journals including Cell, Nature, Nature Cell Biology, Nature Medicine, and Cell Stem Cell. He holds major research grants from NIH, CIHR, SCN, and several health charities. Dr. Rudnicki is a member of the editorial boards of Cell Stem Cell, Journal of Cell Biology, and Stem Cells. He is a founding Co-Editor-in-Chief of the journal Skeletal Muscle. Dr, Rudnicki has also organized many international research conferences and was a founding Director of the Society for Muscle Biology.
For the past 17 years, Dr. Rudnicki has led the Stem Cell Network (SCN), a transformative initiative involving over 175 investigators across Canada. As Scientific Director of the SCN, he has forged a national community that transformed stem cell research in Canada and brought research to the point where regenerative medicine is impacting clinical practice.
Research Overview
Dr. Rudnicki has discovered a protein called Wnt7a as a potential treatment for Duchenne due to its ability to repair muscle damage. He intends to work on delivering this protein through the circulation so it can reach all muscles in the body. His lab is investigating exosomes, small vesicles found naturally in our bodies responsible for delivering information between cells.
Through this funded project, this team will engineer new versions of exosomes carrying Wnt7a to provide this therapy to muscle cells with the hopes of stimulating the muscle’s own capacity for regeneration and growth regardless of mutation.
Dr. Guy Odom
University of Washington – Seattle, WA
“Phenotypic screening of deimmunized DMD gene therapy vectors”
About Dr. Guy Odom
Dr. Guy L. Odom is an Associate Professor in the Department of Neurology at the University of Washington School of Medicine. He received a M.Sc. degree in microbiology, immunology and parasitology at the Louisiana State Health Science Center, New Orleans, LA in 1998, and a Ph.D. in molecular & cell biology at Tulane University in 2005 under the mentorship of Dr. Prescott Deininger with a focus on genomic instability and mobile DNA mechanisms.
Dr. Odom has long had ‘gene therapy’ on the radar, in 1996 as a graduate student he co-authored his first publication in the field. The overall premise of this study was to use transient CD4+ immune suppression to permit re-administration of E1-adenoviral vectors in mice. Following graduate school in 2005, Dr. Odom transitioned to the pacific northwest having accepted a post-doctoral fellow position at the University of Washington (Seattle), in the laboratory of Dr. Jeffrey S. Chamberlain where he emersed himself in the field of Duchenne Muscular Dystrophy (DMD) and viral vector gene transfer technologies having received funding from the NIH and the MDA.
Dr. Odom’s current research continues to evaluate DMD pathogenesis and novel therapeutics for DMD, striving to develop a better understanding of the disease progression, inherent responses at the cellular and genomic levels, and the development of improved gene therapy technologies. Recently deimmunization has emerged as a technology that combines computational protein redesign methods with immune epitope data to engineer vectorized biologics with highly reduced immune liabilities. This research has included the use of physiological measurements at the cellular, single muscle, or whole organismal levels by incorporating sonography, electrophysiological and magnetic resonance imaging techniques. Other interests include muscle stem cell biology, transcriptional regulation, metabolomics, proteomics and combinatorial gene therapy approaches in animal models of DMD.
Research Overview
Gene therapy is a very promising treatment for Duchenne. It works by introducing a smaller version of the dystrophin protein (micro or mini dystrophin), which is the protein lacking in individuals with Duchenne. Recent clinical trials have shown some individuals experience severe side effects due to an immune response to this microdystrophin being introduced through this therapy.
Dr. Odom’s team aims to find a way to circumvent this immune response by engineering utrophin variants to allow improved function and “immuno-silence” portions of the micro-protein. They hope to develop a safer, more productive version of a therapeutic protein to treat Duchenne muscular dystrophy.
Dr. Louis Kunkel
Boston Children’s Hospital – Boston, MA
“A novel therapeutic approach for Duchenne Muscular Dystrophy centered on the NOTCH pathway modulation of Muscle Satellite Cells”
About Dr. Louis Kunkel
Dr. Kunkel is an internationally recognized geneticist with years of experience and scientific success in the understanding of the basis for muscular dystrophies. He received a B.A. from Gettysburg College and his Ph.D. from Johns Hopkins University. Over the past four decades Dr. Kunkel has devoted his career to understanding the molecular basis, and developing therapy, for neuromuscular disorders.
Dr. Kunkel is universally recognized for his 1986 identification of dystrophin as the causative gene in Duchenne muscular dystrophy. His current work centers on developing dystrophin independent therapies for Duchenne muscular dystrophy to complement existing therapies currently in development. He has received numerous awards for his research including membership to the National Academy of Sciences and The American Academy of Arts and Sciences. Dr. Kunkel received the 2009 March of Dimes Prize in Developmental Biology for this pioneering work on muscular dystrophy. He leads a long-standing effort to develop novel therapies.
Research Overview
The decline of motor function due to muscle breakdown is a hallmark sign of Duchenne muscular dystrophy. The root cause is the lack of the protein dystrophin. Yet, what if you could improve a patient’s muscle regeneration independently of the amount of dystrophin protein?
Dr. Kunkle’s team has discovered a biochemical pathway called the Notch pathway. This pathway is a master regulator of muscle satellite cells directly responsible for muscle regeneration. Based on these findings, his lab intends to find a Duchenne therapy that could benefit all boys and young men with Duchenne regardless of their specific mutation.
Funded Projects in 2021
Dr. Niclas Bengtsson
University Of Washington – Seattle, WA
“Development of gene regulatory cassettes that enable safe- and efficient in vivo dystrophin gene-editing in muscle stem cells.”
About Dr. Niclas Bengtsson
Dr. Niclas Bengtsson is an Assistant Professor in the Department of Neurology at the University of Washington School of Medicine. He received a M.Sc. degree in biomedical engineering at the Royal Institute of Technology in Stockholm, Sweden in 2003, and a Ph.D. in molecular cell biology at the University of Florida in 2009.
For the past 10+ years his research has been focused on developing novel and effective treatments for muscle diseases, in particular Duchenne muscular dystrophy (DMD). This research has included the use of MRI techniques to non-invasively evaluate dystrophic muscle pathology and treatment outcomes; studies of basic muscle stem cell biology and transplantation; and gene therapy & gene editing using viral vectors to deliver therapeutic genes in animal models of DMD.
Research Overview
Our research is focused on understanding key mechanisms responsible for pathologies observed in muscle disorders (particularly the muscular dystrophies), and on developing effective treatments to halt- or reverse muscle disease using gene therapy. As a part of the Wellstone Muscular Dystrophy Research Center at the University of Washington, we have designed promising methods that rely on CRISPR/Cas gene editing to correct genetic mutations and improve muscle health in Duchenne muscular dystrophy.
Through our ongoing collaboration with Dr. Stephen Hauschka, we have also developed effective approaches to limit gene therapy & gene editing to muscle tissue, thereby drastically reducing the risk of unintended treatment side effects.
Current research efforts include expanded use of several different technologies that improve or enable genomic correction in both muscle tissues and in muscle stem cells. This also includes investigations of new methods that enhance the overall safety of gene editing and offer expanded applicability to other genetic muscle degenerative conditions. Several innovative platforms are currently being evaluated that allow for early screening of novel approaches and facilitate validation in model systems prior to clinical translation.
Research Update
Dr. Bengtsson’s project is designed to find ways to activate genes, specifically in muscle stem cells. During the first year of his study, his team has identified regions within genes that are active only in muscle stem cells and which could be assembled into regulatory cassettes (RCs) able to control therapeutic gene activation. Further quantitative testing will be done to identify the best cassettes before moving forward with experimentation in animals. All necessary animal models have been acquired and are currently being bred to generate the necessary number of animals to support the proposed studies.
Dr. Natasha Chang
McGill University – Montreal, QC
“Inducing stress granule formation in muscle stem cells to treat DMD.”
About Dr. Natasha Chang
Dr. Natasha Chang is an Assistant Professor in the Department of Biochemistry at McGill University. She obtained her Ph.D. with Dr. Gordon Shore at McGill University studying BCL-2 family proteins and their role in regulating the cell survival autophagy pathway. Her studies highlighted a critical role for basal autophagy in the maintenance of skeletal muscle homeostasis.
Dr. Chang performed her postdoctoral training in the laboratory of Dr. Michael Rudnicki at the Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. During her postdoctoral fellowship, she made seminal contributions establishing the role of the dystrophin-glycoprotein complex in regulating muscle stem cell fate. Importantly, she demonstrated that dystrophin deficiency in muscle stem cells leads to altered epigenetic gene regulation in the mdx mouse model of Duchenne muscular dystrophy.
Dr. Chang’s research program at McGill investigates the molecular regulation of muscle stem cell biology in healthy and degenerative contexts with a focus on strategies to enhance stem cell function to treat muscle diseases.
Research Overview
The Chang laboratory at McGill University is focused on understanding the complex biology of muscle stem cells. Muscle stem cells play an important role in supporting the maintenance and health of skeletal muscle, a tissue that is capable of remarkable regeneration and repair. Our research also examines how muscle stem cell biology is impacted in the context of muscle diseases such as Duchenne muscular dystrophy (DMD).
DMD is a devastating degenerative disease that affects 1 in every 5,000 Canadian male births. Patients with DMD suffer from progressive muscle weakening and atrophy, which results in reduced mobility and ambulation, and eventual death from heart muscle and breathing complications. To date, there remains no effective cure for DMD. Our research program aims to harness the regenerative potential of muscle stem cells as a therapeutic avenue for treating DMD.
Importantly, emerging research studies have found that DMD stem cells do not function as healthy muscle stem cells, and their dysfunction plays a role in disease progression. Our research utilizes DMD models and patient cells to understand how stem cell function is altered in DMD muscle stem cells. Using this knowledge, we are also investigating novel strategies that target muscle stem cells in DMD to restore their ability to make muscle and enhance regeneration. Our research provides a proof-of-concept for stimulating muscle stem cells as a treatment strategy for patients with DMD.
Research Update
Dr. Chang’s team has made considerable progress in their research project, “Inducing stress granule formation in muscle stem cells to treat DMD.” They have optimized several molecular and cell biology assays that will allow them to understand the mechanism of action of the small molecule inhibitors they employ to improve muscle differentiation. Moreover, validation of these inhibitors in mouse models of Duchenne muscular dystrophy is currently underway. Their funding from Defeat Duchenne Canada has provided their research team with invaluable opportunities to support postdoctoral fellows’ training and graduate and undergraduate students.
Dr. Ronald Cohn
The Hospital For Sick Children (SickKids) – Toronto, ON
“Simultaneous DMD gene editing and upregulation to restore protective levels of full-length dystrophin in the treatment of DMD duplication mutations.”
About Dr. Ronald Cohn
Dr. Ronald Cohn has served as President and CEO of the Hospital for Sick Children (SickKids) in Toronto, Canada, since May 1, 2019. Dr. Cohn joined SickKids in September 2012 as the Chief of the Division of Clinical and Metabolic Genetics, Co-Director of the Centre for Genetic Medicine, and Senior Scientist at the SickKids Research Institute. He became the Inaugural Women’s Auxiliary Chair in Clinical and Metabolic Genetics in April of 2013 and joined the Department of Molecular Genetics at the University of Toronto. In 2016, he was appointed Chief of Paediatrics at SickKids and Chair of Paediatrics at The University of Toronto.
Dr. Cohn received his medical degree from the University of Essen, Germany. After his postdoctoral fellowship at the Howard Hughes Medical Institute in the laboratory of Dr. Kevin Campbell, he moved to Baltimore, where he was the first combined resident in pediatrics and genetics at Johns Hopkins University. He subsequently joined the faculty of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, where he became the director of the world’s first multidisciplinary centre for Hypotonia, which has earned national and international recognition.
Dr. Cohn was also the director of the medical genetics residency program at Johns Hopkins. He has received numerous awards, including the David M. Kamsler Award for outstanding compassionate and expert care of pediatric patients in 2004, the First Annual Harvard-Partners Center for Genetics and Genomics Award in Medical in 2006, and the NIH Young Innovator Award in 2008.
Over the last few years, Dr. Cohn has developed an interest in applying the concept of Precision Child Health to the care of children. His own research focuses on implementing genome editing technologies for the treatment of neurogenetic disorders.
Research Overview
Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disease with no cure and treatment being limited to symptom management and delay of disease progression. Dystrophin is a protein essential to muscle integrity. Without enough of it, muscles accumulate damage and weaken over time. Mutations in the gene encoding dystrophin prevent the expression of this protein in muscles, leading to the onset of DMD. Of all the types of DMD-causing mutation, duplications are the second most common.
With major advancements in CRISPR/Cas9 genome editing technology, the underlying genetic causes of DMD are now feasible to correct. We recently utilized CRISPR/Cas9 to remove a duplication mutation and recover dystrophin in DMD mice. While the mice greatly improved, dystrophin levels remained too low to completely prevent DMD.
We believe that increasing the amount of dystrophin protein is necessary to achieve complete disease protection. This project will therefore focus on a new strategy that combines our unique duplication removal approach with dystrophin upregulation into a single therapy. We aim to accomplish this by fusing Cas9 to activator proteins, enabling simultaneous correction of the DMD mutation and an increase in expression of the newly repaired dystrophin gene.
Presently, we have demonstrated this Cas9 fusion protein can still efficiently edit the duplication target for removal while also upregulating the dystrophin protein in mouse cells. Our next step is to evaluate this strategy in our DMD duplication mice and compare its effectiveness to our previous approach.
We anticipate this combined strategy will result in dystrophin reaching levels sufficient to prevent the progression of, and possibly reverse, DMD. If successful, this would be the first demonstration of such a combined approach in an animal. The therapeutic impact of dystrophin upregulation would also be shown, which may be applied to enhance other genome editing strategies and existing therapies for DMD. We firmly believe the results of this work would represent a meaningful step towards a cure for DMD as it effectively treats the underlying cause of the disorder.
Research Update
Dr. Sachiko Sato
Université Laval – Quebec City, QC
“Development of a Monosaccharide Therapy Using N-Acetylglucosamine to Mitigate Duchenne Muscular Dystrophy.”
About Dr. Sachiko Sato
Dr. Sato graduated from the Faculty of Pharmaceutical Science, Chiba University. After working as a research assistant in the toxicology department of Japan Hoffmann-la-Roche Research Center, she joined as a postgraduate student in the laboratory of Dr. Akira Kobata, the Institute of Medical Science, the University of Tokyo, Japan, in 1987. She also worked in the laboratory of Dr. R. Colin Hughes, MRC: National Institute for Medical Research in London, UK.
She obtained her Ph. D. from the University of Tokyo in 1994. As a postdoctoral fellow in the laboratory of Dr. Ron Kopito, Stanford University, she was involved in the work on cystic fibrosis. This work established the precedent that a genetic disease can be remediated by a chemical mean for the first time. This concept has been now elaborated as a “corrector” treatment for cystic fibrosis.
This paradigm shift concept using a small molecule for a genetic disease therapy remains engraved in her research mind. She became the principal investigator of the laboratory of glycobiology in Research Center for Infectious Diseases, assistant professor of the Faculty of Medicine, Laval University, Quebec, Canada, in 1999, and full professor since 2010. She is also the director of the Bioimaging platform since 2003. While her research interest has been the role of galectins in innate immunity, the focus of her laboratory recently has been shifted to the study of the therapeutic potential of galectins for the treatment of muscular dystrophies after her laboratory accidentally found the role of galectin-3 and N-acetylglucosamine, which increases the functions of galectin-3, in both myogenesis and muscle functions.
Research Overview
Our ultimate goal of the research program is to develop the use of orally administered N-acetylglucosamine (GlcNAc) as a therapy for ALL patients with Duchenne muscular dystrophy.
An eccentric contraction is the action of an active muscle lengthening under load, for example, when walking downhill. Repeated eccentric contractions are one cause of muscle injury. Muscle fibers are attached to the basal lamina through multiple protein-protein and protein-oligosaccharide interactions to protect against contractions.
The most critical attachment is through the interaction between laminin in the basal lamina and unique oligosaccharides attached to a-dystroglycan, a component of the dystrophin-glycoprotein complex (DGC), which links to the cytoskeleton of muscle fibers. This sugar-mediated interaction provides jelly-like adhesion of muscle fibers to the extracellular matrix and acts as a shock absorber against tension since the oligosaccharides are intrinsically hydrophilic and structurally flexible. Thus, from both intracellularly (dystrophin) and extracellularly (a-dystroglycan), DGC plays a unique shock cushioning role, providing mechanical stability to the muscle membrane to withstand the contraction forces.
Muscles of Duchenne muscular dystrophy (DMD) patients lack the expression of dystrophin, which leads to the reduced levels of DGC complex and a-dystroglycan on the sarcolemma. In other words, DMD muscles lack extracellular and intracellular shock absorbers to tolerate the forces of contraction and relaxation. Their myofibers are not properly fixed to the basal lamina and detach from it during contraction, leading to muscle damage. Fiber degeneration is counter-balanced by myogenesis at the expense of adult myogenic cells. The constant degeneration of muscle fibers eventually overwhelms the capacity of myogenesis. A lack of dystrophin also impairs myogenesis itself. To improve the quality of life, some possible approaches to delay DMD progression are strengthening muscle fiber attachments to the cell matrix to protect from eccentric contractions and increasing the efficiency of myogenesis.
Our previous results indicated that intraperitoneal treatment (administered through the abdominal cavity) with the monosaccharide GlcNAc for 10 days could counteract the progression of DMD in a mouse model of the disease. Further, our latest preliminary results suggest that 30-days oral treatment with GlcNAc reduced muscle damage. In vitro, GlcNAc (but not glucosamine) increased the efficiency of myogenesis. Notably, GlcNAc is found in human milk at high levels.
A 52-week toxicology study in rats (2.5 g/kg body weight/day, equivalent to 0.6 g/kg/day in humans) and a 4-week clinical trial (6 g/day) in patients with inflammatory bowel disease suggest that GlcNAc is safe. The specific aims of this proposed project are thus to obtain preclinical data to determine the effective oral doses and the efficacy of long-term treatment with GlcNAc for preventing the progressive degeneration of skeletal muscle and heart in mouse models of DMD, in preparation for phase I/II clinical trials.
Research Update
Two-Year Fellowship Grant in Partnership with PPMD
Parent Project Muscular Dystrophy (PPMD), a US non-profit organization leading the fight to end Duchenne muscular dystrophy (Duchenne), and Defeat Duchenne Canada, Canada’s leading charity fighting to defeat Duchenne, announced a collaborative research award of $172,000 (CAD) in support of a two-year Clinical Fellowship in Duchenne Endocrinology and Bone Fragility. The award will sponsor the fellowship of Dr. Kim Phung under the guidance of Dr. Leanne Ward, Professor of Pediatrics and Research Chair in Pediatric Bone Health at the University of Ottawa.
Infrastructure Grant: Satellos Bioscience
Defeat Duchenne Canada provided a research partnership and infrastructure grant to support the development of Satellos’ novel approach to treating Duchenne.
Satellos scientists are developing small molecule drugs that they believe will restore faulty regeneration and repair observed in the muscles of patients with Duchenne and potentially other degenerative muscle disorders. The company’s drug candidates regulate the activity of an enzyme, codenamed PTP-X, which Satellos discovered is involved in controlling muscle stem cell function, allowing these stem cells to properly divide and repair damaged tissue that accumulates in the muscles of Duchenne patients.