MDA Planning New Gene Therapy Trials

TUCSON, Ariz., Feb. 28, 2002 — The Muscular Dystrophy Association has given scientists a $2.2 million grant to prepare for a new gene therapy trial in people with MD.

MDA began a gene therapy trial for limb-girdle MD (LGMD) in 1999, but the trial was halted by a death in an unrelated gene therapy trial at the University of Pennsylvania in Philadelphia. Since then, MDA has been seeking an appropriate group of investigators to begin a new trial using more advanced gene therapy techniques.

Meanwhile, an MDA-funded scientist has made a "microgene" that may prove suitable for gene therapy in the fatal childhood disorder Duchenne muscular dystrophy (DMD).

The new LGMD grant was awarded to gene therapy expert Barry Byrne of the Powell Gene Therapy Center at the University of Florida in Gainesville and molecular biologist Kevin Campbell of the University of Iowa in Iowa City.

Jerry Mendell, co-director of the MDA clinic at Ohio State University in Columbus, plans to use technology developed by Byrne and Campbell to launch a new LGMD trial at Ohio State.

"We're very excited about working with these three institutions, and hope to have a new LGMD trial under way within two years," MDA Director of Research Development Sharon Hesterlee said.

LGMD is a genetic disease that leads to muscle wasting, primarily in the shoulders, hips, and upper arms and legs. In many cases, it's caused by genetic defects in one of four small muscle proteins called sarcoglycans.

"Sarcoglycan-deficient" LGMDs are ideal gene therapy candidates because the genes are small enough to fit into an adeno-associated virus (AAV), considered among the safest and most effective vectors (gene-delivery vehicles).

In MDA's 1999 gene therapy trial, a small number of people with sarcoglycan-deficient LGMD received muscle injections of AAV carrying a normal sarcoglycan gene. The procedure was safe, but gene delivery to muscle cells was low, according to Mendell, who performed the injections.

Since then, vector technology has improved, and it's now possible to design more potent AAV. Byrne and Campbell will use the $2.2 million to develop new AAV versions, and test the viruses' safety and gene-delivery capacity in animals.

They'll also manufacture AAV at the quantity and purity necessary for testing in humans.

Meanwhile, MDA is also laying the groundwork for a clinical trial of AAV-mediated gene therapy for DMD, a form of muscular dystrophy that typically leads to cardiac or respiratory failure by age 25. Dystrophin — the gene that's defective in DMD — is too large to fit into AAV, but recently scientists have made smaller versions of the gene that retain its essential parts.

In the March issue of Nature Medicine, Jeffrey Chamberlain of the University of Washington in Seattle says that he's made the smallest dystrophins yet, called microdystrophins. When delivered by AAV to leg muscles of DMD mice, the microdystrophins largely reversed the muscle-wasting process, Chamberlain said. DMD mice genetically engineered to produce microdystrophin were also protected from wasting of the diaphragm, a muscle that controls breathing.

MDA's Hesterlee estimates that preparations for a gene therapy trial in DMD, including studies in larger animals and the production of custom-designed, clinical-grade AAV, could take two years.

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases. For more information, call (800) 572-1717 or go to www.mda.org.