DMD: Gene-Changing 'Cocktail'

Success of 'exon-skipping' strategy in dogs bodes well for treatment of human DMD

by Quest Staff on March 17, 2009 - 9:00pm

Scientists 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, have successfully treated dogs with a disease closely resembling Duchenne muscular dystrophy (DMD) , using a molecular treatment strategy called "exon skipping." The strategy is simultaneously under development in human patients.

The investigators, who were partially supported 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.

“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.

What’s exon skipping?

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.

Eric Hoffman
MDA-supported researcher Eric Hoffman

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

The dystrophin gene, composed of DNA that carries instructions for making the dystrophin protein, is among the largest known genes. A finalized set of genetic instructions for dystrophin contains 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 hides the error-containing exons from the cell's "view" in such a way that they're skipped over, and the remaining, correct instructions surrounding the region are spliced together. The spliced instructions allow for production of nearly normal, functional protein that's free of genetic errors.

Two clinical trials, one in the Netherlands and the other in the United Kingdom, recently have 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, provide "proof of principle" for the strategy, but they only targeted a single muscle and weren't designed to show functional benefit.

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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.

‘Promising message for DMD’

In the experiments whose results were published March 16 in Annals of Neurology, three dystrophin-deficient beagles 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 was assessed by a 15-minute timed running test and by a combined functional score. All dogs that received the exon-skipping compounds ran faster after the treatment, while their untreated littermates became slower over the same period of time.

Scientists also saw marked improvements in the microscopic appearance of the muscle tissue in the treated dogs, as well as 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.

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