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November 27, 2002

Myostatin-Blockers Improve Muscle Function in Dystrophic Mice

(Philadelphia, PA) - An antibody that blocks the myostatin gene may aid in treating muscular dystrophy by pushing muscle precursor cells into making more muscle. According to researchers at the University of Pennsylvania School of Medicine, the Ja16 mouse antibody blocks myostatin protein, which increases body weight and muscle mass along with a significant decrease in muscle degeneration in mouse models for Duchenne muscular dystrophy (DMD).

The findings, reported in the November 28th issue of Nature, offer support for a novel approach to treating muscular dystrophy while circumventing many of the problems associated with conventional gene therapy.

"This strategy differs from gene therapy in that it actually doesn't try to replace a faulty gene, instead it works around the problem by producing more functional muscle as a compensatory mechanism," said Tejvir S. Khurana, MD, PhD, of Penn's Department of Physiology. "Potentially, this approach may be useful in combination with other types of therapies to slow the progression of muscular dystrophy and other muscle wasting diseases."

Naturally occurring mutations in the myostatin gene were first noted about 200 years ago in the Schwarzenegger-like musculature of the Belgian Blue breed of cattle. The sequence or exact identity of the gene itself was only identified about five years ago in mice. The current report focuses on blocking mouse myostatin in a mouse model of muscular dystrophy.

Many species including humans also have myostatin, and the researchers believe that blocking myostatin is one way to get Duchenne muscular dystrophy sufferers to grow more muscle. "In principle, the approach is doable in humans, if the right reagents are generated, since humans do have this protein," said Khurana, who also has an appointment in the Pennsylvania Muscle Institute, a university-wide multidisciplinary group that investigates muscle and cell motility.

The approach, however, also has its limitations. It did not improve the susceptibility of muscles to damage related to muscular dystrophy pathology. Additionally, the researchers do not know if blockading myostatin will deplete pre-existing stem/muscle progenitor cell pools faster.

"It could be like putting a turbocharger on your old compact car - you'll get performance, but it may eat all of your gas and deteriorate your engine in the process," said Khurana. "If the Ja16 antibody depletes stem or precursor cells, then perhaps we may need to use it as judiciously pulsed doses or, perhaps, not at all."

Khurana and his colleagues believe that the longer-term studies that they plan to undertake will help address these issues. For the time being, however, the Ja16 antibody, which was developed in mice, will likely not work in humans or other DMD animal-models.

Duchenne's muscular dystrophy is one of the most frequent inherited diseases of men, affecting one in 3,500 boys. DMD occurs when the dystrophin gene, located on the short arm of the X-chromosome, is broken. Since males only carry one copy of the X-chromosome, they only have one copy of the dystrophin gene. Without the dystrophin protein, muscle is easily damaged during cycles of contraction and relaxation. While early in the disease muscle compensates by regeneration, later on their progenitor cells of muscle cannot keep up with the ongoing damage and healthy muscle is replaced by non-functional fibro-fatty tissue.

Sasha Bogdanovich and Thomas Krag were the lead authors of the study; other Penn researchers include Elisabeth R. Barton and Linda D. Morris of the Department of Physiology, and Rexford S. Ahima of the Department of Endocrinology. Co-author Lisa-Anne Whittemore is from the Musculoskeletal Sciences Department of Wyeth Research in Cambridge, Massachusetts.

The research conducted in this study was supported in part by a grant from the Wyeth Research/Genetics Institute.

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Editor's Note: Dr. Khurana is a paid consultant for Wyeth Research/Genetics Institute, however, he does not own stock in Wyeth.






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