PROJECTS FUNDED BY JESSE’S JOURNEY – 2016
Principal Investigator: Dr. Ronald Cohn (The Hospital for Sick Children, University of Toronto, Toronto ON)
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.
Principal Investigator: Dr. Jérôme Frenette (Université Laval, Laval QC)
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.
Principal Investigator: Dr. Bernard Jasmin (University of Ottawa, Faculty of Medicine, Ottawa ON)
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.
Projects Receiving Ongoing Funding from Jesse’s Journey
Principal Investigator: Dr. Louise Rodino-Klapac (The Research Institute at Nationwide Children’s Hospital, Columbus OH)
Gene replacement therapy is a treatment strategy that is currently being tested in the clinic to help boys with Duchenne muscular dystrophy (DMD). The Rodino-Klapac research group is able to put the gene (Dystrophin) for this disease into a virus and transfer the gene to the muscle. They have completed one trial in the biceps muscle of six patients using this treatment. This first study showed the way for success in the future. A critical obstacle that remains for successful treatment of DMD is the presence of scar tissue in the muscles of DMD boys. Scar tissue forms very early and could limit how effective gene replacement will be. Therefore, the Rodino-Klapac group is also developing a treatment to prevent or block formation of scar tissue, and test the effectiveness when combined with DMD gene replacement. Combined therapy will be more effective in helping boys with DMD.
Principal Investigator: Dr. Volker Straub (University of Newcastle upon Tyne, Newcastle upon Tyne UK)
Loss of the DMD gene (Dystrophin) leads to elevated calcium levels in muscle, which further damages the muscle. The Straub research group is developing a treatment to combat both, with a combination of an improved exon-skipping therapy (with greater efficacy in heart) and a drug that reduces calcium in muscle. This will determine whether combined treatment has benefit over exon-skipping alone.
Principal Investigator: Dr. Daniel Skuk (CHU de Quebec Research Centre, Laval Quebec)
Cells capable of forming muscle, if genetically normal, could be transplanted into the muscles of patients with Duchenne muscular dystrophy (DMD) to:
(a) Correct the genetic cause of DMD (replace Dystrophin), which is important to stop the deterioration of patients.
(b) Reconstruct the muscles that are destroyed by the disease. This is the only way by which patients with severe handicap could improve.
These aspects are the two pillars of cell therapy for DMD – The Skuk research group is working on both, using their expertise with cell therapies in monkeys (the best model for pre-clinical research in transplantation) to progress towards efficient clinical protocols for DMD patients.
Principal Investiagtor: Dr. George Dickson (Royal Holloway-University of London, London UK)
Gene therapy for DMD aims to compensate for the lack of the DMD gene (Dystrophin) by transferring a working dystrophin micro-gene into the muscle using modified viral vectors as they are very efficient carriers. Experiments done in animal models of this disease showed that there is likely a need to re-administer these viral vectors to guarantee a life-long treatment. Unfortunately, the body responds to re-administration by attacking the external shell of viral vector and neutralizing its effects. The Dickson group is testing a new method to make the body tolerant to the viral vectors so that they can be re-administered multiple times, guaranteeing a life-long treatment to DMD patients. They are planning the first European gene therapy-based clinical trial for DMD.
Principal Applicant: Dr. Jerry Mendell (The Research Institute at Nationwide Children’s Hospital, Columbus OH)
Presently, therapies for Duchenne muscular dystrophy (DMD) are making great headway to correct skeletal muscle dystrophin deficiency. Unfortunately, treatment for the heart lags behind. Nowhere is this better demonstrated than in a recent exon skipping study by Mendell JR et al. (Ann Neurol 2013), using a DNA “Band Aid” (Eteplirsen) produced by Sarepta Therapeutics. This clinical trial showed that once Eteplirsen is started, stability and leg function is maintained in DMD patients. However, eteplirsen did not have a similar stabilizing effect on heart function in these boys. Thus, in the current study, Dr. Mendell and his research group are working to develop a gene therapy approach to restore dystrophin to the heart of mouse and porcine models of DMD.
Principal Applicant: Dr. Dongshen Duan (The Curators of the University of Missouri, Columbia MO)
Duchenne muscular dystrophy (DMD) is caused by many different mutations in the dystrophin gene. Attempts to rescue muscle function include the development of dystrophic “microgenes” to replace the mutated dystrophin gene. To date, dozens of first-generation dystrophin microgenes have been generated and found to rescue muscle function in mice. However, none of these have been shown to rescue muscle function in large animal models of Duchenne (canine) nor in patients. To overcome this problem, the Duan group has developed a 2nd-generation canine microgene in which structural defects identified in the first-generation microgene have been corrected. The new microgene has now been tested in dogs and found to improve muscle function. The Duan group will now develop and test a human 2nd-generation dystrophin microgene and test it in adult DMD dogs. Once validated, this microgene will be ready for use in clinical trials in patients.
Principal Applicant: Dr. Toshifumi Yokota/Haifang Yin (University of Alberta, AB)
Summary of Research Project: A promising therapy for Duchenne muscular dystrophy (DMD) is exon skipping – this therapy uses short DNA molecules that act like “Band Aids” that target the mutated part of the dystrophin gene. To date, 2 different types of exon skipping trials have been conducted in patients. Unfortunately, neither of these trials restored significant dystrophin levels in the heart, and thus not will not extend the lifespan of DMD patients. The Yokota group has now developed new DNA-like molecules in which muscle or heart-targeting molecules have been added. These targeting molecules have been designed to be effectively delivered body-wide to muscle tissues and heart, and thus have immense potential to rescue both muscle and cardiac function.
Development and implementation of a Canadian national registry for Duchenne muscular dystrophy. – Dr. Craig Campbell, University of Western Ontario and Children’s Hospital of Western Ontario, London, ON
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 $8 million in the most promising research projects across North America, including:
- London – University of Western Ontario
- 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