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Positioned to aid muscular dystrophies

Five-year grant establishes collaborative center for cellular research, genetic counseling, education and the development of muscular dystrophy therapies
Dr. Stephen Tapscott seated in his lab
Dr. Stephen Tapscott is co-principal investigator of a five-year grant that will establish a collaborative "center of excellence" for the study and treatment of muscular dystrophies-a group of genetic diseases characterized by weakness and degeneration of muscles that control movement. Photo by Todd Mcnaught

Fred Hutchinson and the University of Washington will receive up to $6.5 million in funding to develop therapies or cures for muscular dystrophies, a group of genetic diseases that result in muscle weakness and wasting.

The five-year grant-one of three in the nation-will establish a "center of excellence" that includes two research projects at each institution and three core facilities. The core facilities will refine tools for gene therapy of the disease, provide genetic coun-seling for patients and their families, and administer a seminar series and other educational activities.

Dr. Jeffrey Chamberlain, professor of neurology at UW, is principal investigator of the grant, and Dr. Stephen Tapscott, investigator in the Human Biology Division, is co-principal investigator. Dr. Marie-Terese Little, a staff scientist in Dr. Rainer Storb's lab in the Clinical Research Division, will lead one of the four research projects.

"It is important to establish centers that will cooperate nationally to develop the resources necessary for future clinical trials in the muscular dystrophies and to encourage the transition from basic to pre-clinical to clinical research in these diseases," Tapscott said.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Neurological Disorders and Stroke and the National Institute of Child Health and Human Development contributed $5 million to establish the center. The Muscular Dystrophy Association, a private health agency, will provide up to $1.5 million in additional funding. This is expected to help draw additional local collaborators. The Muscular Dystrophy Community Assistance, Research and Education Act, passed by Congress in 2001 mandated creation of the centers.

Research goals

The muscular-dystrophy center will encompass basic research on cells to characterize the abnormal genes that cause the diseases. It will also conduct studies with animal models to develop gene therapy that could correct the underlying chromosomal defects, said Tapscott, also a professor of neurology at UW. The ultimate goal is to translate such findings into therapies for patients with muscular dystrophies, for which no known cures exist.

"A major part of our efforts will be to determine whether gene-delivery approaches that have been developed for muscular dystrophies are safe and potentially effective enough to be tested in preliminary clinical trials," he said. "In addition, the grant will help to provide the structure that will make it possible for additional investigators at both institutions to conduct research on these diseases."

Degenerative disease

Muscular dystrophy refers to a group of genetic diseases characterized by weakness and degeneration of muscles that control movement. The Duchenne form is the most common type to affect children, primarily boys. The myotonic form is the most prevalent type to affect adults. There are no effective treatments for the diseases; however, most patients undergo physical therapy to alleviate painful muscle contraction. The severity of the diseases varies among patients with prognosis ranging from mild physical impairment with normal lifespan to severe physical disability. Children with Duchenne's typically do not survive beyond their teens or young adulthood.

Fred Hutchinson and UW are well-positioned to develop improved therapies for the diseases because of their collective strengths in the fields of genetics and gene therapy, stem-cell biology and neuromuscular disease, said Tapscott.

Tapscott's own research has focused on factors that control genes required for normal muscle development. Little and Storb, in collaboration with Tapscott, have conducted studies to explore whether blood-forming stem cells have the potential to develop into muscle tissue, a possible therapeutic approach for muscular dystrophies.

Laboratory studies

At UW, Chamberlain has developed gene-delivery systems for transferring healthy copies of the Duchenne gene into patients. Dr. Thomas Bird, a professor of neurology, founded and directs a neurogenetics clinic at the university, where patients and families can undergo genetic testing. Dr. Stanley Froehner, chair of the physiology and biophysics department, has led research to characterize a group of proteins known to play a role in many muscular dystrophies. Dr. Stephen Hauschka, professor of biochemistry, studies stem cells that give rise to muscle tissue.

In addition to laboratory studies, an important component of the muscular-dystrophy center will be to formalize the accrual of patients into research studies and to offer them genetic counseling. Using DNA samples and tissues collected from patients who consent to participate in such studies, Tapscott will study the regulation of genes that affect myotonic dystrophy, whose symptoms can vary considerably among individuals with the disease.

Tapscott said that he and his colleagues expect that the center of excellence will help them to leverage additional funding for muscular dystrophy research. Future projects may include studies that involve the use of sensitive imaging technology to non-invasively monitor the changes in muscle caused by the disease and, hopefully, to assess the success of any future therapies.

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