UF Research: gene therapy helps treat rare form of Muscular Dystrophy in mice

May 17, 2002

GAINESVILLE, Fla. — A University of Florida researcher has used gene therapy to restore muscle strength in mice with a rare incurable form of muscular dystrophy.

The treatment restored strength lost from muscle cells affected by the disease, and the improvement would probably persist for the life of the mice, said Dr. Barry Byrne, a UF pediatric cardiologist affiliated with the UF Genetics Institute. The findings are reported in this month’s issue of the journal Molecular Therapy.

The disease, known as glycogen storage disease type II, is caused by an enzyme deficiency that prevents the body from breaking down the carbohydrate glycogen, used to store energy. The disease causes gradual weakening of muscle and heart tissue.

Byrne, who led the study, collaborated with researchers at Johns Hopkins University and the National Institutes of Health.

“We observed the mice for up to six months and found greater improvement as time went on,” Byrne said. “That’s a significant accomplishment for a genetic disease, and it’s the right proof-of-concept data we need to go forward with studies in humans.”

Trials of the treatment in people may begin in early 2003 pending the outcome of further research investigating the therapy for side effects.

Glycogen storage disease type II affects one in every 20,000 to 40,000 babies born, Byrne said. The therapy could have broader implications, however, because about 50 diseases are caused by enzyme deficiencies that may be treatable with similar gene therapies.

“This disease is caused by a single, defective gene that’s responsible for producing an enzyme known as GAA,” he said. “If cells don’t make enough of the enzyme, glycogen accumulates in the muscles and reduces their ability to contract.”

The heart also is affected, and in the most serious cases, patients die of heart failure, said Byrne, a professor of both pediatrics, and molecular genetics and microbiology at UF’s College of Medicine.

Severity of the disease varies among patients depending on how much enzyme production is impaired. Slight impairment may cause a slow-progressing form of the disease to emerge during adulthood. Total absence of the enzyme is referred to as Pompe’s disease, which is usually fatal during the first year of life.

Currently, no long-term treatments are available for any form of glycogen storage disease, said Byrne, who also co-directs UF’s Powell Gene Therapy Center. Injections of GAA have provided limited relief to patients in clinical trials, but the enzyme must be administered frequently and the treatments are expensive.

Six forms of glycogen storage disease have been identified, each one associated with a different enzyme deficiency, he said. The type II disease is the only form that principally affects skeletal and heart muscle. Its typical symptoms include enlarged heart and liver, muscular weakness and breathing difficulties.

“When we move on to clinical trials with the gene therapy, we hope to work with infant patients suffering from Pompe’s disease because it is so serious,” he said. Researchers will proceed only if they have solid data showing the treatment will improve functioning in all muscles, including the heart.

To deliver the corrective gene, researchers incorporated it into the apparently harmless adeno-associated virus, which enters the cell and begins producing the missing enzyme, Byrne said. A single treatment is expected to be sufficient because correction of the defective gene in one part of the body can lead to sufficient enzyme production for uptake in all the body’s muscle cells.

“It’s too early to predict how our research may be applied elsewhere, but we hope it will at least be useful in addressing the other glycogen storage diseases,” Byrne said.

Gene therapy is one of the most promising approaches for treating glycogen storage disease type II, said Margaret Wahl, medical and science editor with the Muscular Dystrophy Association in Tucson, Ariz.

“We’re very excited about this work Barry Byrne and others are doing because it may one day offer a cure for this devastating disease,” Wahl said.