MDA-SUPPORTED TEAM DEVELOPS NEW GENE THERAPY STRATEGY FOR DUCHENNE MUSCULAR DYSTROPHY

TUCSON, Ariz., Nov. 28, 2000 - In a move that could advance efforts to use gene therapy to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy in children, researchers have safely and effectively delivered a "minigene" to muscle fibers in mice with this disease, the Muscular Dystrophy Association announced today.

MDA grantee Xiao Xiao of the Department of Molecular Genetics and Biochemistry of the University of Pittsburgh was part of a team that devised three minigenes for the dystrophin protein, which is missing in DMD, and successfully delivered them to muscle cells via an adeno-associated virus (AAV). The mouse muscles showed improvement after receiving any of the three genes.

The team will publish results in the Dec. 5 issue of Proceedings of the National Academy of Sciences. The team's paper was posted on the journal's Web site, www.pnas.org, today.

"We're gratified to see this kind of progress in Duchenne muscular dystrophy, our flagship disease," said Dr. Leon I. Charash, chairman of MDA's Medical Advisory Committee. "We've met with several obstacles to doing gene therapy in this disorder, mostly because the gene is extremely large. This group seems to have found a solution."

DMD affects males almost exclusively. It causes progressive loss of muscle function during childhood and adolescence and usually results in death by the 20s from respiratory and cardiac muscle degeneration.

The disease results from a mutation in the X-chromosome gene for the muscle protein dystrophin. Approximately one in 3,500 males are born with a mutation in this gene, which was first identified by MDA-funded scientists in 1986.

For several years, scientists have recognized the safety and effectiveness of delivering therapeutic genes by tucking them into the tiny AAV. The virus has been used to deliver genes in human studies of limb-girdle muscular dystrophy, the blood disease hemophilia and the lung disease cystic fibrosis.

In contrast to other viruses (viral vectors) used to deliver genes, the AAV provokes little or no protest from the immune system and seems to have no other apparent dangerous effects. Its main disadvantage is that it's too small to carry large genes such as the one for dystrophin.

By removing nonessential parts of the dystrophin gene, Xiao's group made three different "minidystrophin" genes that were small enough to fit inside an AAV vector, the smallest dystrophin genes yet created. They injected the gene-carrying AAV vectors into the leg muscles of mice with DMD, known as mdx mice.

While all three minigenes showed some effectiveness in restoring muscle, one was more effective than the others.

Muscle fibers that received the dystrophin minigenes appeared normal in biochemical tests and microscopic inspection, and the integrity of the muscle membrane - the site of the problem in DMD - was restored.

Xiao said his team hopes to move to clinical trials in DMD patients in the near future, noting that the first clinical studies would only be to test the safety of the procedure and would probably target a small foot muscle.

MDA is a voluntary health agency working to defeat neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual private contributors.