In December 2009, MDA awarded $21 million in new research grants for neuromuscular disease research.
MDA's Scientific Advisory Committee (SAC) and Medical Advisory Committee (MAC) meet each fall and spring to review applications for research grants. Applications are scored on the basis of the capabilities of the applicant, the scientific merit of the project, and the proposal's relevance to developing treatments for the diseases in MDA's program. MDA's Board of Directors then reviews the recommendations of the MAC and SAC.
Some highlights of this latest round of awards are described below.
Muscle Stem Cells
Andrew Lassar, a professor in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School in Boston, has been awarded $487,839 to continue his work in muscle stem-cell biology. Lassar and his colleagues will study the regulation of muscle satellite cells, which lie in a dormant state near muscle fibers and become active when needed to repair damaged muscle tissue. Ultimately, the goal is to use this knowledge to develop treatments for muscle diseases.
Lynn Megeney, an associate professor in the Departments of Medicine and Cellular and Molecular Biology at the University of Ottawa and Ottawa Hospital Research Institute, has been awarded $372,780 to continue his work in this area. Megeney and his colleagues will study the role of a protein called caspase 3, which limits the ability of muscle repair cells called satellite cells to remain in a stemlike state until they're needed. Being able to regulate whether and when these cells mature and become muscle cells and when they remain stemlike could have important implications for the treatment of degenerative muscle diseases.
Muscular Dystrophies in General
Kevin Campbell, professor and chair of the Department of Molecular Physiology & Biophysics at the University of Iowa in Iowa City, has been awarded $517,814 to continue his work in muscle biology. With this new grant, Campbell and colleagues will study the glycosylation (a process involving the addition of sugar molecules) of a muscle protein called dystroglycan. Defects in the glycosylation process are known to underlie some forms of congenital muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD).
Jill Rafael-Fortney, an associate professor in the College of Medicine School of Biomedical Science at Ohio State University in Columbus, has been awarded $387,656 to investigate a new treatment for heart failure in muscular dystrophy. Heart problems are a common feature of many forms of MD. Rafael-Fortney and her colleagues have previously identified a deficiency of a heart-muscle protein called claudin 5 as a likely cause of some of the heart problems seen in MD, and they will now continue with these studies. Their goal is to see whether raising claudin 5 levels could treat or prevent MD-associated heart failure.
Duchenne Muscular Dystrophy
Erica Reeves, vice president of research at Validus BioPharma, a Rockville, Md., biotechnology company, has been awarded $360,000 to continue developing a medication for Duchenne muscular dystrophy (DMD) that mimics the beneficial but not the harmful actions of corticosteroid drugs now in use for this disease. Corticosteroid drugs (such as prednisone and deflazacort) are widely used to dampen inflammation in several diseases, including DMD. In DMD, corticosteroids have been found to slow the loss of muscle tissue and prolong walking. However, they also have several side effects, such as significant weight gain, high blood pressure and personality changes. Therefore, there's a need to improve on these medications.
Michael Jirousek, chief scientific officer at Catabasis Pharmaceuticals in Cambridge, Mass., biopharmaceutical company, also has been awarded $150,000 to develop molecules that combat inflammation in DMD.
Limb-Girdle Muscular Dystrophy
Jerry Mendell, director of the Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital in Columbus, Ohio, and co-director of the MDA clinic at that institution, has been awarded $458,814 to move toward testing of whole-limb delivery of a therapeutic gene to treat type 2D limb-girdle muscular dystrophy (LGMD2D), which results from a deficiency of the alpha-sarcoglycan protein in muscle fibers. Mendell has received MDA support for clinical research in MD for many years. Recently, he and his and colleagues have received MDA funding to deliver the gene for alpha-sarcoglycan via intramuscular injections to people with LGMD2D. The experimental treatment appears to be safe and to allow for production of the needed protein from the new gene. The ultimate goal of the new funding is to move toward whole-limb delivery via injection of therapeutic genes into the bloodstream. It is hoped that this whole-limb gene delivery approach can be developed into a function-improving treatment for this form of MD.
Myotonic Muscular Dystrophy
Thomas Cooper, the S. Donald Greenberg Professor of Pathology at Baylor College of Medicine in Houston, has been awarded $346,661 for studies in myotonic muscular dystrophy (MMD, or DM). Cooper and his colleagues are developing compounds that may be able to target and destroy toxic the genetic instructions that lead to type 1 and type 2 MMD.
Amyotrophic Lateral Sclerosis
Steven Perrin, chief executive officer and chief scientific officer at the Amyotrophic Lateral Sclerosis Therapy Development Institute (ALS TDI) in Cambridge, Mass., has been awarded $2.5 million to develop gene therapy for amyotrophic lateral sclerosis (ALS), a disease in which muscle-controlling nerve cells in the brain and spinal cord are lost, causing paralysis. Although most cases of ALS are not genetic (inherited), it is believed that there are therapeutic genes, from which therapeutic proteins can be produced, that may improve symptoms and prolong life. The ALS TDI receives a significant portion of its support from MDA, via its Augie's Quest initiative.
Jeffrey Rothstein, a professor of neurology at Johns Hopkins University in Baltimore, where he directs the MDA/ALS Center, has been awarded $377,802 to continue his research in ALS. Rothstein, who has been receiving MDA support for ALS research for two decades, has specialized in the study of nervous-system support cells called astroglia. There is evidence that astroglia can help protect the nerve cells that die in ALS. Rothstein's new MDA-supported project is to find compounds that help increase production of these potentially protective cells.
James Rusche, senior vice president of research and development for the Repligen Corp., a Waltham, Mass., drug development firm, has been awarded $731,534 to continue developing an experimental compound for the treatment of Friedreich's ataxia (FA). FA, a genetic disease that involves degeneration of parts of the nervous system, is caused by a deficiency of a protein called frataxin. The drug that Repligen is developing, designed to increase frataxin levels, belongs to a class of chemical compounds known as histone deacetylase (HDAC) inhibitors.
Fu-Dong Shi, a principal investigator at Barrow Neurological Institute, part of St. Joseph's Hospital and Medical Center in Phoenix, has been awarded $450,000 to continue his work in myasthenia gravis (MG). In this disease, the immune system mistakenly attacks the place where where nerve signals normally reach muscle fibers, leading to fluctuating weakness. This "autoimmune" (self-immune) disease can be treated by general suppression of the immune system and other therapies. However, a treatment that specifically targets only the actions of the immune system that cause the disease would be highly desirable. Shi and his colleagues, who have received significant previous MDA funding, will now focus on Th17 cells, which recent research has shown may play a key role in causing or amplifying autoimmunity.