DNA "Patch” for Canine Form of Muscular Dystrophy Developed -- First Treatment for Human Muscular Dystrophy in Sight

Using an innovative genetic technology that covers up genetic errors, researchers have developed an effective treatment for dogs with the canine version of Duchenne muscular dystrophy, a paralyzing, and ultimately fatal, muscle disease.

The technology, known as "exon skipping," utilizes customized snippets of DNA-like molecules as molecular "patches." These patches cover up mutant DNA sequences that code for making an important muscle protein. The mutant sequences occur in portions of the gene known as exons, which contain the information needed to make the muscle protein. By covering up the mutant regions, the DNA patches allowed the dogs to produce an imperfect--but functional--version of the protein, and considerably improve their muscle functioning.

Earlier studies showed that it was possible to inject the patches into the bloodstream of lab mice and deliver them throughout the animals' bodies. The current study demonstrates that the DNA patches could be delivered by injection throughout the entire body in a much larger animal than a mouse, raising the possibility that they might be successfully delivered throughout the body to human muscles as well. Moreover, the research represents an advance over the earlier efforts in that it was able to use several different kinds of DNA patches. A combination of different patches, known as a cocktail, would be needed to treat most of the human cases of the disease, which can involve many different exons.

The canine version of Duchenne muscular dystrophy occurs naturally in dogs, and affects the same gene that is affected in the human form of the disease. "This is a promising finding," said Duane Alexander, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of the U.S. National Institutes of Health (NIH; Bethesda, MD, USA) institutes that provided partial funding for the study. "It's an important step toward realizing the goal of developing a treatment that could alleviate the symptoms of this disorder."

Muscular dystrophies are a group of disorders causing muscle deterioration and weakness. Duchenne muscular dystrophy occurs almost exclusively in males, affecting 1 in every 3,500. Symptoms begin at about three years of age, with muscle weakness resulting in difficulty walking and talking. Most boys with the condition lose the ability to walk by age 12, and death usually occurs by the early 20s, from heart and respiratory failure.

The study was published online in March 2009 the Annals of Neurology and conducted by Toshifumi Yokota, Ph.D., and Eric Hoffman, Ph.D., from the Children's National Medical Center (Washington, DC, USA), and Shin'ichi Takeda, M.D., Ph.D., from the National Center of Neurology and Psychiatry, Ogawa-Higashi, Kodaira (Tokyo, Japan), as well as other researchers at Children's, Carolinas Medical Center (Charlotte, NC, USA), and the National Center (Tokyo, Japan).

Duchenne muscular dystrophy results from errors in the gene for dystrophin, a key component of muscles. Dr. Hoffman explained that individuals with Duchenne muscular dystrophy vary in the locations and kinds of the mutations occurring in the gene. In addition, many boys with Duchenne muscular dystrophy have mutations that affect multiple exons, and so would require more than one kind of patch. The canines in the study carried a mutation affecting multiple exons. The researchers used a cocktail containing multiple DNA patches to bypass the affected exons.

The patches, DNA-like molecules called morpholinos, are manufactured in a laboratory. Injections of the morpholino cocktail directly into the dogs' bloodstream suppressed deterioration of the animals' skeletal muscles and improved muscle functioning. The injections resulted in widespread production of dystrophin-like protein, at approximately 26% of normal levels. However, the treatment was unable to prevent deterioration of the animals' hearts. The researchers theorized that the muscles of the heart are less porous than the skeletal muscles, and did not absorb adequate quantities of the morpholinos to curb the deterioration.

The researchers reported that other means of delivering the morpholinos to the heart would need to be examined. They added, however, that the study results showed that it would be possible to use a cocktail of morpholinos to patch the multiple mutations that occur in the human form of the disorder.

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