Gene Therapy Cures Muscular Dystrophy in a Mouse Model

Positive results in a mouse model indicate that gene therapy might be successfully used to reverse muscle wasting in human Duchenne muscular dystrophy (DMD).

DMD is the most common form of muscular dystrophy in which fat and fibrous tissue infiltrate muscle tissue, causing eventual weakening of the respiratory muscles and the myocardium. The disease, which almost exclusively affects males, begins in early childhood and usually causes death before adulthood. The disease is caused by a mutation of the dystrophin gene whose protein product is responsible for the connection of muscle fibers to the extracellular matrix through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane). In a complex cascading process involving several pathways, the excess calcium causes the creation of more reactive oxygen species than the cell's oxide-scavenging enzymes can effectively process. This creates oxidative stress within the cell, which damages the sarcolemma and allows more entry points for calcium, and ultimately resulting in the death of the cell. Muscle fibers undergo necrosis and they are ultimately replaced with adipose and connective tissue.

Investigators at Ohio State University (Columbus, OH, USA) worked with a line of mice (mdx) that displayed muscle-wasting symptoms similar to human DMD. They used a gene therapy approach based on a modified Adeno-like virus to insert into the animals the gene for follistatin, a potent inhibitor of myostatin, which is a protein that limits muscle growth. A unique aspect of the study was that both young and old mxd mice were treated.

Results published in the March 11, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences described dramatic effects of the gene therapy. Young mdx mice received a single injection at three weeks of age. When examined after five months, they showed larger body mass and higher muscle weight than did comparison animals. Older mice received the therapy when they were 210 days old, at least a month after they showed significant hallmarks of their disease, including inflammation and fibrosis. When they were 560 days old, the treated mice showed robust muscles, with increased muscle fiber size along with reduced inflammation and less scarring compared to placebo-treated mdx mice. Two years after gene therapy, no effects on reproductive function or cardiac function in the mice were seen.

"These studies are significant given that there was functional effect on muscle enhancement even when treated at later stages in the mouse model,” explained senior author Dr. Brian K. Kaspar, assistant professor of pediatrics at Ohio State University. "Many studies do not evaluate a therapy over a two-year time span. In our studies, the beneficial effects persisted over the two years we evaluated. Furthermore, this long-term study shows that there were no obvious safety problems with either the gene therapy virus or the therapeutic protein, follistatin. This protein led to muscle enhancement, increased strength, and lowered the effects of inflammation and fibrosis. Because of those effects, we believe that it could be potentially useful for older Duchenne muscular dystrophy patients. And these results appear to translate to other muscle wasting diseases and aging, so it has potential to help a larger population of patients.”


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