Gene therapy improves muscle action in mice with muscular dystrophy, researchers say

Tuesday, September 17th 2002, 12:00 am

By: News On 6

WASHINGTON (AP) _The crippling effects of muscular dystrophy were partially corrected in laboratory mice by the insertion of a new gene that restored to the muscles a protein lacking in victims of the fatal disease.

Researchers at the University of Washington, Seattle, fused a gene that makes a muscle chemical with a modified virus and injected the combination into the hind leg muscles of mice that have a disorder that mimics Duchenne muscular dystrophy.

Within a month, the test mice had a 40 percent improvement in muscle action compared to muscular dystrophy mice that received no injection, said Christiana DelloRusso, lead author of the study that appears in this week's Proceedings of the National Academy of Sciences.

``We measured the force produced before and after the muscle is stretched and it was much better with the mice that were injected compared to the ones that weren't,'' DelloRusso said Monday.

Duchenne muscular dystrophy is a muscle-wasting disease caused by the mutation of the gene that produces a muscle protein called dystrophin. The disorder, linked to the X chromosome, is inherited in about one of every 3,500 males born in the United States, and about 12,000 patients are now living with the disease.

The disease originates from a gene that fails to produce dystrophin, a protein that helps the muscles stretch and contract normally. Without this protein, the muscles tear faster than the body can repair them, a process called contraction injury. Over time, the muscles waste away.

Patients generally are diagnosed by age 4, and they usually are using a wheelchair by age 12. Most die in their 20s, although improved care has allowed some patients to live until their early 30s. Muscles in the heart and pulmonary system are affected, generally leading to death from respiratory or heart failure.

To control the disease, researchers are trying to replace the flawed gene with a normal gene that would produce dystrophin.

In the University of Washington study, researchers engineered a virus, called an adenovirus, so that it lacked the genes to make viral particles. The viral genes were replaced by the gene that makes dystrophin. When injected, the virus infects cells and inserts the new gene into the DNA of the target muscle cells.

The researchers injected the virus-gene combination into the hind legs muscles of MDX mice, laboratory animals that develop Duchenne muscular dystrophy. For comparison's sake, some mice received the gene therapy while others received neutral injections.

One month after injection, the legs of the test mice were about 40 percent more resistant to contraction injury than were the other animals' legs.

DelloRusso said an analysis of the muscle around the injection site showed that the tissue was making dystrophin at a level 25 to 30 percent of normal.

Sharon Hesterlee, director of research development at the Muscular Dystrophy Association, said the report by DelloRusso and her colleagues ``is an important paper'' because it showed the technique can improve the muscle action around the injection site.

The disease will not be controlled, however, until researchers find a way to deliver the correct gene to muscles throughout the body, she said.

``The major technical hurdle is that muscle makes up 40 to 50 percent of body mass, and we don't have a good way yet to deliver these genes to all the muscles,'' said Hesterlee, a neuroscientist. ``The virus injected directly into a muscle doesn't really travel very far. For this gene therapy to really be an effective therapy, we're going to have to develop some sort of systemic delivery. That's still a big problem.''

Also, said Hesterlee, there are misgivings about the safety of the adenovirus used as the carrier of the gene. Other studies have shown that the adenovirus can cause serious side effects.

DelloRusso said the study used what is called a ``gutted adenovirus'' because it lacks many of the genes that can cause side effects. But she acknowledged that the safety of the adenovirus would have to be extensively tested before the gene therapy could tested in humans.