MDA-SUPPORTED RESEARCHERS MOVE CLOSER TO "MINIGENE" THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY

TUCSON, Ariz., May 30, 2001 - In a pivotal step toward gene therapy for Duchenne muscular dystrophy (DMD), researchers have shown that a "minigene" can sustain muscle strength in mice that have the disease, the Muscular Dystrophy Association announced today.

The minigene - a compact stand-in for the flawed dystrophin gene that causes DMD - was designed by MDA grantee Xiao Xiao and his research team at the University of Pittsburgh. Recently, Xiao and his group showed they could deliver the minigene to mice with DMD, and now they've found that the treatment largely prevents muscle weakness in the mice.

"Dr. Xiao has made a very exciting advance," MDA Director of Research Development Sharon Hesterlee said. "We knew that the mini-dystrophin gene could get into muscle and produce a mini-dystrophin protein. Now we know that this compact dystrophin can substitute for the normal version, and perhaps preserve muscle function in someone with DMD."

Xiao's colleague, Bing Wang, presented the new MDA-funded study today at the fourth annual American Society of Gene Therapy meeting in Seattle.

Xiao said he expects that gene therapy with mini-dystrophin will be an effective treatment for DMD, an inherited muscle disease that almost exclusively affects males. Each year, about 1 in 3,500 males are born with DMD-causing mutations in the dystrophin gene. The loss of dystrophin protein causes muscle wasting during childhood, and leads to death in the 20s from respiratory and cardiac failure.

For Xiao and other researchers, devising a gene therapy strategy for DMD has been a significant challenge. Many researchers consider the tiny adeno-associated virus (AAV) an ideal vehicle for delivering replacement genes because, unlike other viruses, it provokes little response from the immune system. Unfortunately, the normal dystrophin gene is too massive to fit inside the AAV. To overcome that problem, Xiao removed what he suspected were non-essential pieces of the gene, creating a few different "minigenes."

In an MDA-funded study published several months ago, Xiao showed that those minigenes could cause long-lasting expression of dystrophin protein in mice with DMD, and that the shortened protein helped prevent treated muscles from breaking down.

But would the trimmed-down dystrophin preserve strength in the mice? To answer that question, Xiao treated muscles in the legs of mice, then, seven months later, put them through a rigorous strength test. "It's like arm-wrestling with a really strong guy. It can potentially cause severe damage to the muscle tissue, so it's a vigorous test," Xiao said.

In the test, as expected, muscles from normal mice typically declined to 41 percent of their original strength, while muscles from untreated DMD mice fared much worse by declining to 22 percent of their original strength. But muscles treated with the new gene therapy protocol withstood the challenge as well as normal mice.

"That level of force improvement is very significant and demonstrates that mini-dystrophin can support muscle function," Xiao said. The new results set the stage for clinical trials of mini-dystrophin, but the Food and Drug Administration (FDA) will require further safety studies in mice before such trials can begin, Xiao said.

"We at MDA expect clinical trials for Duchenne and other forms of muscular dystrophy to be very expensive," Hesterlee said. "That's why we've helped develop legislation that would direct the National Institutes of Health to provide more federal funding to muscular dystrophy research." The legislation, called the MD-CARE Act, was introduced in the Senate earlier this month.