Since 1995, Jesse’s Journey has believed in developing strong partnerships with academics and clinicians to fund the most promising research for Duchenne muscular dystrophy. Through their determination and love for their son Jesse, the Davidson family built a legacy endowment fund that has granted 14.8 million dollars across 50 research projects to date.
through our annual research granting process, we have attracted leading Duchenne scientists worldwide, including Canada, the United States, UK, Netherlands and Japan, with a growing number of applications every single year. The growth in scientific funding interest is encouraging for our community because it means there is an increasing commitment to Duchenne science and drug discovery, bringing us hope and one step closer to prevention, treatment, and ultimately – a cure.
Thanks to the vision and commitment of our donors in a year like no other, 2021 marks our largest funding year to date, granting $1.7 million.
The power of community advocacy and donations from supporters – like you – have become an essential ingredient to our research investments. Your gifts allow researchers, like the ones below, to test new knowledge and push the boundaries of science to advance our understanding and ultimately develop new medicines that could change lives. Learn more about the impact of your gifts on the most promising science below.
NEWLY FUNDED PROJECTS IN 2021
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: “Development of gene regulatory cassettes that enable safe- and efficient in vivo dystrophin gene-editing in muscle stem cells.”
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 also 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 enable early screening of novel approaches and facilitate validation in model systems prior to clinical translation.
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: “Inducing stress granule formation in muscle stem cells to treat DMD.”
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 muscle 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 in order 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.
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 to the position of 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 the 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 worlds' 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; 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: “Simultaneous DMD gene editing and upregulation to restore protective levels of full-length dystrophin in the treatment of DMD duplication mutations.”
Duchenne muscular dystrophy (DMD) is a debilitating, 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.
About Dr. 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 main 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: “Development of a Monosaccharide Therapy Using N-Acetylglucosamine to Mitigate Duchenne Muscular Dystrophy.”
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 -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 (-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 -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.
2020/21 Research Grant Announcement
CONTINUED PROJECTS FUNDED IN 2021
Children’s Hospital – London Health Sciences Centre is a lead site for Myoblast transplantation in boys with Duchenne, a project funded by Jesse's Journey in collaboration between Dr. Campbell and Dr. Tremblay. The project is currently under review, stay tuned for further details.
Gene therapy for Duchenne is making great strides. The work undertaken by Dr. Duan and his team aims to address the delivery of these gene therapies so they are can be made affordable and available to many Duchenne patients.
About Dr. Duan
Dr. Dongsheng Duan is the Margaret Proctor Mulligan Professor in Medical Research at the University of Missouri and a fellow of the National Academy of Inventors. He has made many seminal contributions in the field of gene therapy, in particular, in the development of the adeno-associated virus vector and Duchenne muscular dystrophy gene therapy. Dr. Duan has previously received a grant from Jesse’s Journey and we are proud to award him a research grant for his project entitled: “Super AAV for DMD gene therapy in human muscle”.
The fundamental problem in Duchenne muscular dystrophy (DMD) is the dystrophin gene mutation. If we can replace the mutated dystrophin gene with a good one, it will address the genetic cause of the disease and treat DMD at the root. Research in gene replacement therapy has been a longstanding goal for Jesse’s Journey from the very beginning.
After more than three decades of research, investigators have identified adeno-associated virus (AAV) as an ideal vector to deliver a therapeutic gene to patients suffering from inherited diseases. AAV is the name for a family of viruses. There are hundreds of members in the family. They are named AAV1, 2, 3 etc. FDA has recently approved two gene therapy drugs that are made of AAV2 and AAV9.
The AAV2-based drug is currently been prescribed to children who suffer from a rare blindness disease and the AAV9-based drug is currently been prescribed to infants who suffer from an inherited motor neuron degenerative disease.
Two AAV family members are now been tested in Duchenne boys to deliver a miniaturized micro-dystrophin to the muscle throughout the body. These are AAV9 and AAVrh74. In order to treat all muscles in the body, investigators have to inject at least 1015 particles of one of these two AAV vectors to a single patient. While preliminary analyses have revealed promising results, the infusion of trillions of AAV particles has also resulted in life-threatening immune responses and severe adverse reactions (such as liver toxicity) in some patients.
If we can find a new AAV that is much more potent than AAV9 and AAVrh74, we will achieve the same therapeutic efficacy at a much lower dose. This should greatly reduce the risk of adverse reactions and immune responses. The purpose of this project is to identify such a super-potent AAV virus for gene delivery in the human muscle. Besides reducing toxicity, we believe this super-AAV will also greatly reduce the burden of AAV manufacture, and hence making the therapy affordable and available to many more Duchenne patients.
Jesse's Journey in collaboration with Muscular Dystrophy Canada (MDC) are proud to fund Dr. Anthony Gramonlini.
We are developing non-viral vehicles for the delivery of genome editing machinery with specific emphasis on targeting skeletal muscle cells associated with Duchenne muscular dystrophy (DMD). Clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) is a powerful new gene-editing tool. Our objective focuses on generating novel degradable and biocompatible nanoparticles (BNPs), using our U of T patented polyurethane technology. These carriers address limitations with current CRISPR/Cas9 delivery platforms, specifically eliminating the use of immune reactive virus; enables co-delivery of a specific targeting tool; and reduces potential off-target tissue damage; Studies will evaluate the therapeutic corrective capacity of nanoparticles in a DMD mouse model, and establish a technology to enable novel therapies for DMD patients in Canada and abroad.
For the first time ever, Jesse's Journey is granting $1 million dollars to support single project - the clinical trial of vamorolone in Canada. This anti-inflammatory therapy currently under investigation has shown promising benefits, with a better safety profile than traditional corticosteroids. Furthermore, the VBP15-006 trial is focused on collecting data in a broader age population, a major gap in clinical trials today.
About Dr. Hoffman
Dr. Eric Hoffman is a human geneticist and translational researcher focused on neuromuscular disease, and skeletal muscle tissue in health and disease. Currently, he is Associate Dean for Research, School of Pharmacy and Pharmaceutical Sciences, Binghamton University – SUNY. In the private sector, he is co-founder and CEO of ReveraGen Biopharma, co-founder and Vice President of AGADA Biosciences, and co-founder and President of TRiNDS LLC; each company focuses on different aspects of orphan drug development.
The standard of care for Duchenne muscular dystrophy remains high dose corticosteroids (prednisone or deflazacort), as they have been demonstrated to improve muscle strength and prolong ambulation. However, corticosteroids are well-known to have extensive side effects, and the doses given to DMD boys are higher and for longer periods of time than other patients typically prescribed corticosteroids. Thus, the side effects seen by DMD boys are often more severe than other patients taking corticosteroids. Side effects include stunting of growth, bone fragility and bone breaks, mood disturbances, delay of puberty, Cushingoid (moon face) features, hirsutism (extra growth of hair), and others.
Dystrophin replacement strategies hold promise in improving the muscle strength of DMD boys. However, all dystrophin replacement strategies are done in combination with corticosteroids. This is because all the dystrophin replacement strategies use highly modified, semi-functional dystrophin proteins, where inflammation of muscle still occurs, and corticosteroids help reduce this inflammation. Moreover, in gene therapy treatment, corticosteroid doses are often increased over what is normally prescribed to DMD boys in an effort to prevent inflammation caused by the viral vectors used in gene therapy.
What is needed is a safer steroid that still improves DMD patient strength and mobility, and still works with dystrophin replacement therapies, but without the wide range of side effects that prednisone and deflazacort show.
Vamorolone was developed to separate out the benefit from the safety concerns of traditional corticosteroids. Vamorolone is still a steroidal anti-inflammatory, but it is not a corticosteroid or glucocorticoid (e.g. not in the same class of drugs as prednisone or deflazacort). Tweaks of the chemistry of vamorolone led to differences in how it binds ‘receptors’ that mediate its effects on the body. There are two receptors that both corticosteroids and vamorolone bind to the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). When a drug activates the receptor it is called an “agonist”; when it blocks and inactivates the receptor it is called an “antagonist”. Prednisone is an agonist for the mineralocorticoid receptor, and this adds to side effects. Vamorolone does the opposite to the MR – it is an antagonist, and in mice shows heart-healthy activities very similar to eplerenone (a cardiac drug often used in DMD). For the glucocorticoid receptor, prednisone and deflazacort are potent agonists as well, and this mediates both the anti-inflammatory effects (benefit) but also many of the side effects. Vamorolone is a ‘partial agonist’ of the glucocorticoid receptor, where it retains the activities associated with benefit (anti-inflammatory activity) but loses much of the activity associated with side effects. In a word, the tweaks of the chemistry of vamorolone lead to tweaks in how the drug interacts with both GR and MR compared to prednisone and deflazacort.
To date, clinical trials of vamorolone have been carried out in DMD boys, where the boys were young when they entered the trials (4 to <7 years), and were ‘steroid naïve’ (never treated with corticosteroids like prednisone or deflazacort). The young age was important to determine if vamorolone preserved muscle function and the steroid-naïve was important to see if vamorolone developed side effects. If the patients were already treated with prednisone or deflazacort before starting vamorolone, it would be challenging to see if side effects were due to previous treatment with corticosteroids, or due to new treatment with vamorolone. These initial clinical trials have gone well, and are published. Vamorolone treatment led to improvements in strength and mobility over 6 months of treatment, and these improvements were preserved over 1.5 years of treatment. Importantly, key side effects, such as stunting of growth, were not observed with vamorolone treatment; the boys grew normally. This data is supportive of vamorolone having the potential to replace corticosteroid treatment in DMD. Perhaps most importantly, families have been quite satisfied with vamorolone treatment. Of the initial 48 DMD boys treated, the large majority have asked to remain on vamorolone (and not transition to corticosteroids) for over 2.5 years.
A placebo-controlled double-blind clinical trial of over 100 DMD boys, ages 4 to <7 years, steroid naïve, is underway with recruitment in 11 countries at 33 academic medical centers. The COVID-19 pandemic has created challenges for the vamorolone clinical trials, as it has for most all clinical trials, but the study seems to remain on track, and will likely complete the 6-month key endpoint in the fourth quarter of 2020.
In the meantime, the vamorolone study team, as well as many families of DMD, have asked some important questions: Can a DMD boy that is treated with corticosteroids (prednisone, or deflazacort) transition to vamorolone? What will treatment do for boys older than 7 years, or younger than 4 years (broader age range than 4 to <7 years)? The European drug regulatory agency, the EMA, asked the vamorolone team the same questions and wanted a clinical trial initiated to address these questions before considered drug approval for vamorolone throughout Europe for DMD.
The new VBP15-006 clinical trial has been designed to address these questions, and Jesse’s Journey has partnered with ReveraGen BioPharma to enable the activation of the trial in Canadian academic medical centers. Similarly, DuchenneUK has partnered with ReveraGen to activate the trial at sites in the United Kingdom.
VBP15-006 plans to enroll 44 DMD participants, with a broad age range (2 to <4 years; and 7 to <18 years). In addition, older participants can be previously treated with corticosteroids (prednisone or deflazacort). The clinical trial is 3 months long, and then participants can enroll in the expanded access protocol that is already active in Canada for long-term treatment with vamorolone, if the family and their physician wish this.
The funding from Jesse’s Journey is the largest award ever provided by the foundation (Can$1M), and is provided in stages based on ReveraGen achieving key milestones (completion of the trial). Also, the funding is provided under a new ‘return-on-investment’ model for Jesse’s Journey, where the funding will be repaid to Jesse’s Journey based on later drug sales of vamorolone internationally. If vamorolone is successful, Jesse’s Journey will receive over 400% return on its investment in vamorolone. This can then be used to fund the charity and further philanthropic efforts. Other non-profit foundations internationally have partnered with ReveraGen similarly for this and other clinical trials of vamorolone (shared risk, shared benefit model).
Jesse's Journey in collaboration with Muscular Dystrophy Canada (MDC) are proud to fund Dr. Michael Rudnicki.
Duchenne muscular dystrophy is a devastating genetic disorder manifested by progressive muscle wasting and ultimately death around the second decade of life. Injection of a secreted protein called Wnt7a greatly enhances muscle regeneration resulting in amelioration of dystrophic progression. However, based on the its chemical nature Wnt7a cannot be delivered via the blood circulation. We have discovered that Wnt7a is normally secreted on the surface of small vesicles called exosomes during muscle regeneration. Exosomes have been demonstrated to effectively deliver cargo through the circulation to muscle. We will compare the activity of free Wnt7a versus exosomal Wnt7a, we will investigate the mechanism that targets Wnt7a to exosomes, and we will test the ability of exosomal Wnt7a to be delivered to muscle through the circulation. These experiments have the potential to significantly increase the efficacy of Wnt7a for treating Duchenne Muscular Dystrophy, especially when used in combination with gene correction therapies.
Dr. Tremblay’s laboratory aims to develop therapies to treat Duchenne individuals with point mutations affecting about 30% of Duchenne patients. His novel CRISPR approach is important as it addresses corrections to the dystrophin gene that can not be treated by exon skipping therapies.
About Dr. Tremblay
Dr. Jacques P. Tremblay, Professor in the Department of Molecular Medicine at Laval University in Quebec, has been award a research grant for his project entitled: “Correction by CRISPR base editing of point mutations responsible for Duchenne Muscular Dystrophy.”
The laboratory of Dr. Jacques P. Tremblay has been working on the development of a cell and gene therapy for Duchenne Muscular Dystrophy (DMD) since the discovery of the dystrophin gene in 1987. DMD is due to many different mutations in the dystrophin gene, all leading to the absence of dystrophin under the membrane of the muscle fibres. This leads to more frequent breaks of the muscle fibre membrane and to progressive muscle weakness.
Genes are in fact a sequence of pairs of nucleotides, which form the DNA, a double-strand helix. There are four different nucleotides (A:adenosine, T:thymidine, C:cytosine and G:guanine) forming four pairs A:T, T:A, G:C and C:G. Proteins, such as the dystrophin protein, are formed by 20 different amino acids. The genes (i.e., the DNA) code for the proteins. However, since there are only 4 different nucleotides it takes a sequence of three nucleotides (called a codon) to code for one amino acid. However, there are 3 different codons, which are stop codons. They indicate to the cell that the protein is finished.
Tremblay’s laboratory has been mainly working on the transplantation of myoblasts (the cells that form the muscle fibres) derived from a healthy donor as a treatment for all possible mutations in the dystrophin gene. Indeed, these myoblasts contain the normal dystrophin gene and thus introduce in the muscle fibres of the DMD patients the normal gene. This type of treatment is currently in Phase I/II clinical trial in collaboration with Dr. Craig Campbell (London Health Institute). Unfortunately, the main problem of this type of treatment is that because the myoblasts are derived from another person, the patient has to be immunosuppressed with Tacrolimus to prevent rejection. Such immunosuppression increases the risks of cancer and infections. Due to this problem, the human ethics committee has limited participation to patients who are more than 16 years old so that they can give fully informed consent. Health Canada has also imposed that DMD patients should not have a tracheotomy. These two restrictions are greatly impeding the progress of the clinical trial.
An alternative to avoid the requirement for sustained immunosuppression with Tacrolimus is to transplant to the patient his own myoblasts. However, these myoblasts would have to contain a normal dystrophin gene. The dystrophin gene itself is too big to be easily introduced in the patient myoblasts. Some researchers are working on introducing a smaller dystrophin gene, i.e., a micro-dystrophin gene containing the beginning and the end of the gene.
The dystrophin gene contains 79 parts (called exons). These exons are separated by nucleotide sequences (called introns), which do not code for a protein. Different exons are made of sequences of a different number of nucleotides. About 70% of the DMD patients have a deletion of one or several exons. Depending on which exons are deleted the total number of deleted nucleotides will vary. When the total number of deleted nucleotides, which are deleted in not a multiple of 3 nucleotides, the codons, which follow the deletion is changed, i.e., they will not code for the right amino acid. Eventually, one of the modified codons will be a stop codon and the dystrophin protein will be terminated. This dystrophin protein will have an adequate beginning but not an adequate end. This truncated protein will not be able to attach under the membrane of the muscle fibre. This absence of dystrophin leads to DMD. Some researchers are trying to restore the expression of an internally deleted dystrophin gene by deleting additional exons located just before or after the exons deleted in the patient dystrophin gene. This is called exon skipping. The aim of doing these additional deletions is that the total number of deleted nucleotides becomes a multiple of three. When this is the case the amino acids before the deletion and after the deletion are correct. The resulting internally deleted dystrophin protein will be able to attach under the muscle fibre membrane but it will be more or less functional depending on the part of the dystrophin protein, which is missing. This is the case of the Becker patients.
An alternative is to correct the dystrophin gene present in the patient's own myoblasts.
About 30% of DMD patients have a point mutation (i.e., the change of only one nucleotide pair). Very often the mutation of one nucleotide pair results in the formation of a stop codon. Thus, the formation of the dystrophin protein ends prematurely, there is just the beginning of the dystrophin protein and not the end of that protein. Thus, the dystrophin protein is not present under the muscle fibre membrane and the patient is dystrophic just because there is one pair of nucleotides, which is mutated, the rest of the dystrophin gene is perfect! Our objective is to develop therapies for DMD due to such point mutations. A new base editing technique (called PRIME editing) derived from the CRISPR/Cas9 technology permits in principle to modify at will a targeted pair of nucleotides. There is only one article, which has been published about that technology a few months ago. The authors of that article have described the modifications of pairs of nucleotides in several genes but not in the dystrophin gene. The grant that we have obtained from Jesse Journey will permit to my team to test that PRIME editing technology on the dystrophin gene. We will initially test this technique to correct the point mutation present in the MDX mouse model of DMD. We also have a list of the point mutations observed in Canadian DMD patients. These are the point mutations that we will aim to correct. Eventually, this PRIME editing technique would permit to correct the point mutations directly in the myoblasts of the patients to permit the transplantation of the patient's own myoblasts thus avoiding the use of the Tacrolimus immunosuppression. However, our ultimate goal would be to correct the point mutations directly in the dystrophin genes inside the muscle fibres of the patient. The PRIME editing technology may also be used to induce the skipping of exons for the 70% of patients who have a deletion of one or several exons. This would be done by just changing 1 nucleotide at the beginning of the exon(s) to be skipped.
The PRIME editing technique may eventually be used to correct point mutations responsible for hundred of other hereditary diseases due to point mutations.
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Genome-editing is a new promising way to treat many genetic diseases including DMD. Here, we will establish a proof-of-concept in a larger animal model, dystrophic dogs, and apply the same strategy in DMD patient cells for future clinical implementation. To restore a short functional dystrophin protein, at least 3 exons (the part of DNA that carries the information for protein production), exons 6-8, need to be removed. This will lead to functional dystrophin protein production. We will evaluate the efficacy and the safety of the genome-editing in the DMD dog model, especially focusing on the functional recovery of the skeletal muscle and the heart. Also, we will apply the same strategy to the DMD patient cells. Successful completion of this study will open the door for the future clinical translation of genome-editing therapy for DMD patients.
COMPLETED FUNDING IN 2020
Duchenne muscular dystrophy (DMD) is the most common neuromuscular disorder with a life-limiting disease trajectory. Majority of DMD causing mutations are large chromosomal deletions resulting in the absence of dystrophin protein. Despite significant advances in our understanding of the DMD pathogenesis, there is no cure. Recent advances in genome editing technologies have the potential to develop into curative therapies for DMD. Recently we have pioneered an approach to remove duplications within the DMD gene and developed several strategies to correct large chromosomal deletions creating a foundation for treating DMD patients. Due to the lack of available animal models carrying large DMD mutations, we generated two novel mouse models recapitulating large deletions in the dystrophin gene observed in patients. The overall goal of the current project is to develop clinically relevant genome editing strategies to correct DMD causing deletions in newly generated animal models resulting in expression of functional dystrophin.
Jesse’s Journey is one of the original funders of the Canadian Neuromuscular Disease Registry (CNDR) and we are very pleased to be able to fund the CNDR for its 12th consecutive year. The CNDR is a very important disease registry collecting clinical data that will help bring clinical trials to Canada, inform our health care system on standards of care, support treatments for Duchenne in Canada, and an excellent source of information to stay informed if you choose.
About Dr. Korngut
Dr. Lawrence Korngut is a neurologist, clinical neurophysiologist and Director of the Calgary Neuromuscular Program and the Calgary ALS and Motor Neuron Disease Clinic in Alberta. Dr. Korngut has been instrumental in the creation of the Canadian Neuromuscular Disease Registry (CNDR) along with Dr. Craig Campbell, Dr. Jean Mah, Dr. Bigger and other Canadian clinicians in establishing and growing the registry to what it is today.
The Canadian Neuromuscular Disease Registry (CNDR) is a Canada-wide registry of people diagnosed with a neuromuscular disease. It collects important medical information from patients across the country to improve the understanding of neuromuscular disease and accelerate the development of new therapies. Currently, over 4500 neuromuscular patients have registered from across Canada.
Transforming growth factor beta (TGFbeta) plays an important role in causing muscle damage in Duchenne muscular dystrophy (DMD) and is a factor for the bone disease in DMD. The proposed project starts from the idea that TGFbeta released from the skeleton by bone resorption has a negative effect on bones and muscles, as has been shown in several other diseases. We will therefore test whether slowing down bone resorption decreases TGFbeta activity both in DMD muscle and in DMD bone. Using a novel drug, we will also assess whether TGFbeta inhibition specifically in bone has a positive effect in muscles and bones. The results of this study can lead to changes in how current bone-strengthening treatments are given to boys with DMD and can lead to the development of a new treatment for muscles and bones in DMD.
This is the first time Jesse’s Journey is supporting work that is focused on Duchenne patient care related to sexual health. This is an area often forgotten about with very little data in Duchenne and Becker. Dr. Sheriko and Dr. Baxter aim to explore questions and concerns related to gender identity, sexuality and sexual health in individuals with Duchenne and Becker muscular dystrophy.
About Dr. Sheriko and Dr. Baxter
Dr. Jordan Sheriko, Assistant Professor of Pediatrics and Medicine at Dalhousie University in Nova Scotia, and the Medical Director of Pediatric Rehabilitation at the IWK Health Centre, in collaboration with Dr. Carly Baxter has been award a research grant for their project entitled: “A survey of Canadian youth with Duchenne and Becker Muscular Dystrophy exploring gender identity, sexuality, sexual health questions and concerns”.
Dr. Sheriko and his team have created a survey to explore the issues related to sexual health and gender including whether individuals feel their needs are being met. The survey will be mailed out using the Canadian Neuromuscular Diseases Registry (CNDR). The information will help better understand this important topic and give guidance to neuromuscular clinicians on the concerns and experiences of the adolescent and young adult DMD population. Dr. Sheriko and his team hope that this work will form the basis of understanding sexual health and gender issues so that healthcare teams feel confident in asking youth sexual health questions and are able to counsel and provide appropriate information and resources.
Duchenne muscular dystrophy (DMD) is caused by frame-shifting mutations in the DMD gene. "Frame shift" means that the normal code that tells the cell how to make dystrophin protein no longer make sense. BMD mutations retain the reading frame and produce an internally deleted, but functional protein. Because DMD is a monogenic disorder, gene editing strategies such as CRISPR/Cas9 can be exploited to directly edit the mutant DMD gene to turn a DMD patient into a BMD patient. Here, we develop non-viral based technology to deliver CRISPR and other nucleic acids to enable delivery to DMD muscles. Once the nanoparticle carrying the CRISPR system reaches the muscles, CRISPR enters and edits the DMD gene. In our proposal, we will use a CRISPR platform that we designed that has the potential to treat approximately 60% of DMD patients.
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