March 16, 2009

SUCCESS OF STRATEGY IN DOGS BODES WELL FOR TREATMENT OF HUMAN MUSCULAR DYSTROPHY

TUCSON, Ariz., March 16, 2009 - Scientists have successfully treated dogs with a disease closely resembling Duchenne muscular dystrophy (DMD) , using a molecular treatment strategy called "exon skipping," the Muscular Dystrophy Association (MDA) announced today. The strategy is simultaneously under development in human patients.

Watch a video of MDA-supported researcher Eric Hoffman discussing this new development. Watch Video: 56K • 256K • 512K

Investigators at Children's National Medical Center in Washington, Carolinas Medical Center in Charlotte, N.C., and the National Center of Neurology and Psychiatry in Tokyo, supported in part by MDA, showed intravenous injections of a "cocktail" of laboratory-developed compounds coaxed the muscle fibers of three DMD-affected dogs to produce functional dystrophin protein, the absence of which causes the disease. The strategy in general (although not this specific cocktail) could potentially apply to 80 percent to 90 percent of DMD patients, the researchers say.

“These findings demonstrate that exon skipping is a very real and promising treatment strategy for Duchenne muscular dystrophy,” MDA Senior Vice President Sharon Hesterlee said.

“Many efforts have focused on treating dogs with muscular dystrophy, as it is widely expected that what works in the dogs will work in humans," said Eric Hoffman, professor of pediatrics at Children's National Medical Center and an MDA grantee.

About DMD

DMD is the most severe of the childhood-onset muscular dystrophies. This genetic disease affects males almost exclusively and causes gradual weakening of the voluntary skeletal muscles, including the respiratory diaphragm and other breathing muscles, and of the heart. Survival beyond age 30 is rare.

About Exon Skipping in DMD

In 1986, a group of MDA-supported scientists, including Hoffman, identified flaws in the gene for the muscle protein dystrophin as the underlying cause of DMD.

Since then, strategies to either replace or compensate for the loss of dystrophin, including exon skipping, have been the focus of MDA's DMD research program.

The dystrophin gene, composed of DNA that carries instructions for the dystrophin protein, is among the largest known. Genetic instructions for dystrophin contain 79 sections, or "exons," in the form of a molecule called messenger RNA.

Genetic errors can occur in messenger RNA in any exon. The most severe errors cause the rest of the genetic message to be scrambled or not made at all.

Exon skipping is a strategy that masks the error-containing exons in such a way that they're skipped over, and the remaining, correct instructions surrounding the region are spliced together. The newly spliced instructions allow for production of nearly normal, functional protein that's free of genetic errors.

Two clinical trials in Europe have recently shown that intramuscular injection of either of two exon-skipping compounds appears safe in boys with DMD and that it can lead to production of dystrophin. These trials, which used compounds developed with MDA support, provided "proof of principle" for the strategy, but they only targeted a single muscle and weren't designed to show functional benefit.

In contrast, the DMD dog experiments delivered exon-skipping compounds systemically, via intravenous injections, resulting in bodywide production of significant levels of dystrophin and improvement in the dogs' functional abilities.

In addition, the human trials targeted only one exon, while the dog experiments targeted two consecutive exons.

About These Experiments

In the experiments reported on today in Annals of Neurology, three dystrophin-deficient dogs were each given intravenous injections of a cocktail of exon-skipping compounds either weekly or every other week. All three showed new dystrophin production in all examined muscles, although the degree of production varied. The average dystrophin protein production level was greatest in the dog given seven weekly doses of 200 milligrams per kilogram of the exon-skipping cocktail, causing dystrophin levels to rise from zero to 26 percent of normal.

Functional improvement of the treated dogs compared to untreated littermates was assessed by a 15-minute timed running test and by a combined functional score. The untreated littermates became slower over the treatment time, whereas all treated dogs ran faster after treatment. The scientists also saw marked improvements in the microscopic appearance of the muscle tissue and other measures of muscle health.

"Overall, our findings provide a promising message for DMD patients," said Shin’ichi Takeda of the National Institute of Neuroscience and Psychiatry in Tokyo, a senior author on the paper.