PROJECTS FUNDED BY JESSE’S JOURNEY – 2018
Duchenne Muscular Dystrophy (DMD) is a life-limiting genetic disorder associated with progressive muscle degeneration. Despite significant progress in our understanding of the development of the disease, no cure has been found. Standard treatment with corticosteroids targets the symptoms of the disorder, but not the underlying cause, and is associated with significant side effects. We will explore the potential of a revolutionary genome engineering technology called CRISPR/Cas9 to target the underlying genetic mutation and protein expression deficiencies associated with DMD. Specifically, we will use the technology to increase expression of utrophin—a protein which can compensate for the loss of dystrophin in DMD—and remove duplicated regions of the dystrophin gene in patients cells and newly created animal models for DMD. This research will provide the necessary evidence base to support further exploratory studies into the use of CRISPR/Cas 9 as a new, more effective treatment option for patients with DMD.
Dr. Cohn was approved for another project entitled “Therapeutic gene editing approaches for the treatment of DMD caused by exonic deletions”
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.
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
DMD is the most prevalent genetically-inherited neuromuscular disorder affecting ~1 in 3500 boys. This disease is severe since children become wheelchair-bound by adolescence and death usually occurs in their second/third decade of life. Several approaches are being developed to counteract the deleterious effects of DMD including gene therapy, cell transfer and exon skipping. An alternative strategy consists in utilizing a protein expressed in dystrophic muscle which, once expressed at appropriate levels and at the correct location, could compensate for the lack of dystrophin.An ideal candidate for such a role is utrophin because it is very similar in its properties to dystrophin. Additionally, muscle fibers from DMD patients express utrophin endogenously. Therefore, studies aimed at deciphering the mechanisms involved in controlling utrophin expression in muscle are essential to pave the way for the rational design of pharmacological interventions focused on increasing the endogenous expression of utrophin in dystrophic muscle fibers.
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.
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.
Families of those with DMD and affected young men themselves understand this to be an exciting time in the history of DMD. A number of treatments have been developed sufficiently in animal models that clinical studies are occurring aimed at a broad range of potential disease mechanisms from non-sense mutation read-through, exon skipping, myostatin inhibition and myoblast transfer. Given that DMD is a rare disease and many of these therapies are specific to certain genetic variants, it is critical that the DMD community (patients, families, clinicians and researchers) organize themselves in such a way to facilitate clinical trials, such that high-quality, meaningful studies can be completed. One way in which to do this is through the development of databases or registries. Realizing accurate DMD databases has been a major priority recently for both scientific groups (TREAT-NMD) and parent/patient driven organizations (Duchenne Connect). A well functioning database serves as a valuable tool in which to bring treatments developed in the laboratory ultimately to the patient. This project is allowing the development and implementation of a Canadian national database for DMD which will provide the foundation for Canadian patients with DMD to be a part of local and international research efforts.
Since 1995, Jesse’s Journey has granted more than $10 million to the most promising research projects across North America, including:
- London – Western
- 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