Spotlight on Research 2011

June 2011 (historical)

Study Shows Sustainability of Gene Transfer Therapy for Limb-Girdle Muscular Dystrophy

Research supported, in part, by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) expands upon the initial success of a gene transfer study for treating limb-girdle muscular dystrophy type 2D (LGMD2D). The new study, reported in the Annals of Neurology, showed the expression of the protein alpha-sarcoglycan, which is deficient in people with the LGMD2D form of the disease, can be sustained for at least six months.

In 2009, a research team led by Jerry R. Mendell, M.D., director of the Center for Gene Therapy at the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, reported positive initial results for their Phase I safety and efficacy trial to transfer the alpha-sarcoglycan gene to three LGMD2D patients via a vector virus called AAV1¹. The gene was delivered into a small foot muscle of the participants, resulting in the production of alpha-sarcoglycan for three months without significant immune system complications. In the new, longer study, three more LGMD2D patients received the alpha-sarcoglycan gene via the AAV vector. Two of these three patients expressed alpha-sarcoglycan for a 6-month period, and one of the two showed an increase in muscle fiber diameter, suggesting a reversal of the disease process. Alpha-sarcoglycan was not expressed in the third participant, a result that the investigators attributed to pre-existing immunity to AAV. As in the earlier study, no serious side effects occurred in any of the patients.

Under normal conditions, alpha-sarcoglycan helps to form a scaffold with other proteins to give structure to muscle membranes. But, when there is not enough alpha-sarcoglycan, this supporting structure breaks down, and the muscle membrane becomes unstable. This causes the muscle fibers to deteriorate, and LGMD2D patients to become weaker.

Although there are currently no effective treatments for LGMD2D, Dr. Mendell is increasingly optimistic that his team’s work may provide one. “We now have some longer-term data that increase the prospects for using gene transfer to restore muscle function not only in this condition, but in other forms of muscular dystrophy,” he says. “We now need to move forward with additional trials to confirm the efficacy of this approach.”

LGMD2D occurs when a person inherits mutations in both copies of the alpha-sarcoglycan gene. The disease usually begins in childhood with limb muscle weakness and wasting, and calf-muscle hypertrophy.

Partial support for the study was provided by the NIAMS-funded University of Pittsburgh Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center. Other supporters include the National Institute of Neurological Disorders and Stroke, part of the NIH, and the Muscular Dystrophy Association.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

¹ Mendell JR, et al. LGMD 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol 2009 April; DOI: 10.1002/ana.21732.

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Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010 Nov; 68(5):629-38.

The study was registered at www.clinicaltrials.gov as NCT00494195.