Spotlight on Research 2009

August 2009 (historical)

Study Shows Safety of Gene Therapy for Limb-Girdle Muscular Dystrophy

Researchers supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have shown that gene therapy may be possible for a potentially severe form of limb-girdle muscular dystrophy (LGMD), a group of disorders that often begin in childhood and cause wasting of skeletal muscles, particularly those around the hips and shoulders.

In the particular form of LGMD studied — classified as LGMD 2D — patients are unable to produce normal levels of a protein called alpha-sarcoglycan, which attaches to other proteins to form a scaffold structure, called a protein complex, that stabilizes muscle membranes.

When a patient is deficient in alpha-sarcoglycan, the protein complex breaks down and the muscle membrane becomes unstable. As a result, muscle fibers deteriorate and the affected muscle tissue is easily damaged by everyday activity. When the muscle fiber deterioration exceeds the muscle's ability to repair itself, the patient loses muscle fibers and becomes increasingly weaker over time. Currently, there are no effective treatments for LGMD 2D.

The 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, believed that inserting a gene that expresses alpha-sarcoglycan into affected muscles could reverse the deficiency, thereby maintaining the protein complex that stabilizes the muscle membrane. The team designed a Phase I safety trial to test delivery and expression of the alpha-sarcoglycan gene and to assess immune responses against the alpha-sarcoglycan protein or the viral vector.

Three patients with LGMD 2D received the gene therapy in the form of a virus called AAV1 designed to deliver the alpha-sarcoglycan gene directly to the muscle cells. The AAV1 virus was injected into a small muscle in one foot and a saline control solution was injected into the same muscle in the other foot. Neither the patient nor the researchers knew which side received the gene therapy until all of the data were collected and analyzed.

The findings were better than the researchers had hoped. Muscle sampled up to 12 weeks after injection showed the patients had no immune response to the protein and very little response to the virus.

"One of the most interesting parts about this study," said Mendell, "is we did have some inflammatory response in the muscle, but the cells recruited there seemed to be undergoing natural programmed cell death. They didn't invade the muscle fibers and they didn't have any effect on the gene expression. That has not been shown before in any human gene therapy."

In addition, the muscles that received the therapy showed positive gene expression in examined tissue. "We reached 60 to 70 percent of muscle fibers showing gene expression," said Mendell. "We think it is more than enough to potentially improve strength. If we could get that in all of the muscles, we would have a clinically meaningful outcome."

The researchers now have begun a second phase of this study, which will look at the longer-term effects of the therapy in three additional patients. "A six-month trial would give us powerful data to help determine if we have an immune response or if we would lose gene expression," Mendell said. "If we can extend it for six months, it really sets the stage for using gene therapy with this type of virus and this gene to achieve long-term gene expression."

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Reference: Mendell JR,. Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR. LGMD 2D gene therapy restores alpha-sarcoglycan and associated proteins. Annals of Neurology. 2009 April; DOI: 10.1002/ana.21732.