Saving muscles with genes
ANDREW KILBARGER was 4 years old when his preschool teacher realized something was terribly wrong. He didn’t run or jump, and he couldn’t pedal a bike. When his parents had him checked by his pediatrician, even the physician was stunned by the diagnosis: Andrew had Duchenne muscular dystrophy, a rare, inherited, degenerative muscle disorder that afflicts 30,000 in the U.S., almost exclusively boys.
Sufferers’ faulty genes don’t produce dystrophin, a vital structural protein the body needs to build muscles. Without it, muscles deteriorate. By adolescence, victims must use a wheelchair, and they usually die in their 20s from respiratory or cardiac muscle failure.
Last month, Andrew, who just turned 9, became the first patient in an experimental gene therapy trial that may eventually help him escape this grim fate. Doctors at Columbus Children’s Hospital in Ohio injected dystrophin genes in the muscle of one of his arms, and a sham injection into the other.
After about six weeks, they’ll take samples of muscle cells from each arm and examine them for evidence of dystrophin production. They’ll also assess muscle strength and look for signs of any harmful reactions. Before the end of the year, five other boys each will receive one injection of the dystrophin gene.
“Gene therapy is the Holy Grail that could eventually cure this disorder,” says Sharon Hesterlee, a neuroscientist and director of research development for the Muscular Dystrophy Assn. in Tucson. “This study is the long-awaited first step in that direction.”
The experiment is one of a number of studies being conducted around the country that may finally make gene therapy -- introducing genes into a person’s body to treat disease -- a clinical reality. Twenty years ago, such experiments held out the tantalizing possibility of a cure for dozens of inherited ills, such as Duchenne muscular dystrophy and cystic fibrosis: The defective genes simply would be compensated for by adding functional ones.
The technological hurdles proved daunting, however. “It turned out to be very difficult to actually get the genes into cells where they would do any good,” Hesterlee says. And in one well-publicized 1999 incident, an 18-year-old patient died from a severe immune reaction to a virus that was used by doctors to ferry foreign genes into his body.
In recent years, scientists have reported success in curing two deadly immune disorders. However, three of the children in one of the trials developed leukemia when a cancer-causing gene was activated by the therapy, and one of them died.
Scientists now think they can surmount some of the obstacles surrounding gene therapy. They’ve created specially modified viruses that can shuttle genes to the proper place in the body (be it heart, liver or muscles) but don’t provoke an adverse immune response or toxicity. Starting with a harmless variant of a common cold virus called adeno-associated virus, or AAV, researchers have created customized gene carriers that home in on different parts of the body.
“Essentially, we’ve engineered microscopic FedEx trucks with ZIP Codes that go to specific targets,” says R. Jude Samulski, director of the University of North Carolina Gene Therapy Center in Chapel Hill who helped develop this technology. “Some [carriers] prefer the liver, others the lungs, while some have an affinity for muscles.”
Duchenne muscular dystrophy is caused by only one mutant gene, so it is a good first candidate for gene therapy. However, the dystrophin gene -- which is the largest gene in the human genome -- doesn’t fit inside these viral freighters. To solve that, research teams working independently at the University of Washington in Seattle and the University of Pittsburgh developed miniature versions of the dystrophin gene. These mini-genes were then shoehorned inside an AAV “shuttle” designed to carry the gene to muscle cells.
Results in animals have been encouraging. An October 2005 study conducted by Chinese and American scientists, for example, showed that one injection of the specially designed AAV carrier delivered the dystrophin genes to muscles and the heart in hamsters suffering from a form of muscular dystrophy.
The gene transfer improved their cardiac and muscle functions to normal levels. It also significantly prolonged their lifespan: Treated animals survived beyond the 48-week duration of the study, compared with an average of 37 weeks for diseased hamsters that didn’t receive gene therapy.
The study in which Andrew Kilbarger is participating is an early, preliminary step toward forging a cure for his disease. If this approach proves safe and prompts the persistent production of dystrophin in muscle cells, researchers will move ahead with a more ambitious study -- injecting the genes into the bloodstream.
“We have to deliver the genes to all the crucial muscles,” says neurologist Dr. Jerry R. Mendell, director of the Gene Therapy Center at Columbus Children’s Research Institute in Ohio, who is conducting the clinical trial.
“Then we can have a system that will make a real difference for kids.”
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Treating the symptoms
Currently, there is no specific treatment to halt or reverse the more than 30 types of muscular dystrophy. But doctors use drugs and other therapies to ease symptoms. Corticosteroids such as prednisone slow muscle degeneration. Anticonvulsants can control seizures, and immunosuppressants may delay some damage to dying muscle cells. Orthopedic appliances are often used for support, and corrective orthopedic surgery also can help. Other treatments include physical, respiratory and speech therapy.
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-- Linda Marsa
