Since 1995, Jesse’s Journey has strongly believed in strong partnerships with academics and clinicians to fund the most promising research for Duchenne muscular dystrophy. This focus and fundraising effort have brought us to granting more than $13.1 million across 45 research projects. We have attracted applications from leading Duchenne researchers from all over the world including the United States, UK, Netherlands and Japan, and in 2020, we received the highest number of grant applications in our 25-year history!
Our vision is a world free from the physical and emotional anguish of Duchenne muscular dystrophy. We know we can get there, and we know that research is the key. But we also know this: if research doesn’t get funded, it doesn’t happen and if we don’t advocate for access to treatments once they are discovered, our boys and young men will suffer. We would not be here if it weren’t for the generosity and vision of our donors – thank you for your continued support to #defeatduchenne.
Thanks to the support of our donors, 2020 marks our largest funding year to date, granting $1.6 million.
NEWLY FUNDED PROJECTS IN 2020
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).
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.
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.
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 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.
2019/20 Research Grant Announcement
CONTINUED PROJECTS FUNDED IN 2020
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.
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.
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.
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.
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.
Jesse's Journey in collaboration with Muscular Dystrophy Canada (MDC) are proud to fund Dr. Micheal 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.
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.
COMPLETED FUNDING IN 2019
Gene therapy for DMD aims to compensate for the lack of dystrophin by transferring a working dystrophin micro-gene into the muscle using modified viruses called adeno-associated virus (AAV) vectors as they are very efficient carriers. Experiments made in animal models of this disease showed that we likely need to re-administer these AAV to guarantee a life-long treatment. Unfortunately the body responds to the AAV re-administration attacking the external shell of AAV and neutralizing the effect of these vectors. Here we propose to further develop a new method to make the body tolerant to the AAV so that they can be re-administered multiple times guaranteeing a lifelong treatment to DMD patients. We are now planning the first European gene therapy-based clinical trial for DMD. This study could generate an agent resolving the issue of AAV re-administration in this clinical trial for DMD and in clinical applications for other diseases.
Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. The absence of dystrophin activates a variety of cellular pathways that promote the accumulation of calcium inside the cytoplasma in muscle cells. Excessive cytosolic calcium triggers proteolysis and membrane lysis. Breakdown of cellular machinery leads to muscle death. Most cytosolic calcium in muscle is removed by sarco/endoplasmic reticulum calcium ATPase (SERCA). Unfortunately, SERCA activity is reduced in DMD. We found that SERCA activity reduction is caused by over-expression of the SERCA inhibitor, sarcolipin (SLN). Experimental reduction of SLN expression in genetically engineered mice or by adeno-associated virus (AAV) gene therapy significantly reduced muscle disease in dystrophin/utrophin double knockout mice. Here we will test this highly promising therapy in the canine model. If confirmed, it could lead to rapid initiation of a Phase I trial in DMD patients.
Read Dr. Duan's full published paper here.
While there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a specific biological pathway that synchronously regulates the physiopathology of bone and skeletal muscle remains unclear. We have studied a combination of therapeutic drugs that have already been tested or approved for osteoporosis (bone) and asthma (smooth muscle) and other tissues and have applied our knowledge to create new treatments for several forms of skeletal muscle diseases. The present project is aimed at understanding how osteoprotegerin (a bone protein) and β2 agonists rescue dystrophic muscles in a mouse model of Duchenne muscular dystrophy (DMD). We have high hopes that a better understanding of the cellular pathways involved with osteoprotegerin as well as combined treatments will open up new therapeutic avenues for DMD and possibly other neuromuscular diseases.
To learn more about Dr. Frenette's work, watch a short video here.
Duchenne Muscular Dystrophy (DMD) is a highly aggressive disease with early onset (2-6 years old), which ultimately leads to premature death of patient in the second or third decade of their life. No cure or effective treatment is currently available or forthcoming for DMD. In this project we will pursue a novel therapeutic approach, which aims at mobilizing the existing muscle stem cells to expand and repopulate the diminishing muscle cell population. This will be achieved by targeting a pathologically active STAT3 protein with most potent direct STAT3 inhibitors developed to date. Discovered in the group of Dr. Gunning, these inhibitors will be evaluated in cell and animal models of the disease and further optimized for the treatment of DMD. With a goal of identifying a drug candidate for human trials, this project will also uncover whether an anti-STAT3 therapy is a generally viable approach for the treatment of DMD.
Find out more about Dr. Gunning's research here
Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease. Although no definitive treatment exists, there has been significant improvements in treating respiratory failure in patients with DMD resulting in a life expectancy of 20-30 years of age. However, these patients are now living long enough to suffer from cardiac complications and most die from heart failure. To meet this unmet medical need, we developed a novel platform to conduct a high-throughput drug discovery screen with heart cells generated from human stem cell lines engineered to harbor a dystrophin mutation. In this proposal we will test and identify the ability of the most promising compounds, identified in our screen, to halt or reverse abnormalities found in human and rat heart cells that lack dystrophin. Together, the results from these experiments will provide new preclinical data to inform a clinical trial of cardio-protective drugs in DMD patients suffering from heart failure.
Since 1995, Jesse’s Journey has granted more than $13.1 million to the most promising research projects around the world, including:
- University of Pittsburgh – Dr. Johnny Huard
- OHRI (Ontario Health Research Institute) – Dr. Mike Rudnicki
- UBC (University of British Columbia) – Dr. Fabio Rossi
- CHUQ – Quebec City’s Centre Hospitalier Universitaire de Quebec – Dr. Jacques Tremblay and Dr. Daniel Skuk
- Children’s Hospital – Columbus, Ohio – Dr. Jerry Mendell
- LHRI (Lawson Health Research Institute) – CNDR (Canadian Neuromuscular Database – Dr. Craig Campbell
- University of Missouri – Dr. Dongsheng Duan
- University of Ottawa – Dr. Bernard Jasmin
- Children’s Hospital, Columbus, Ohio – Dr. Louise Rodino-Klapac
- Children’s Hospital, London – Dr. Craig Campbell