Gene therapy reverses muscular dystrophy in animal model

Researchers have proven that gene therapy can reverse the pathological features of muscular dystrophy in an animal model. Before, gene therapy had only been able to prevent further muscle-wasting in mice. “We expect to build on these results in the continuing search for a way to treat a horrible disease. Our results indicate that gene therapy could be used not only to halt or prevent this disease, but also to restore normal muscle function in older patients,” says Dr. Jeffrey S. Chamberlain, professor of neurology at the University of Washington School of Medicine in Seattle.

Chamberlain is the senior author of the paper describing the results, which will be published in the Proceedings of the National Academy of Sciences online Early Edition the week of Sept. 16 to 20.

Duchenne muscular dystrophy is an X-linked genetic disorder that strikes one of every 3,500 newborn boys. The genetic disorder means the body does not produce the dystrophin protein, which is necessary for the structural support of muscle. Without this protein, muscles weaken to the point where the victim cannot survive. There is no specific treatment against any form of muscular dystrophy, except for supportive measures, such as physical therapy, assistive technology and corrective surgery. Boys and men with the disorder usually die from respiratory failure before they can turn 25.

Researchers have been looking for many years for ways to introduce the dystrophin gene into the body of patients to replace the missing gene. In doing so, researchers have developed a strain of mice who lack the dystrophin gene. In the past, researchers have been able to insert the gene into newborn mice via adenoviral vectors. But those vectors have many viral properties, and results have been limited because adult mice and mice that have begun to develop symptoms of the disease developed a sharp host immune response that eliminated the therapeutic gene.

The results have also been limited because the dystrophin gene is large, and until now, there has not been a good way to deliver the entire gene and have it remain in the muscles of the mice. Last spring, Chamberlain and colleagues reported they were able to deliver a “micro” version of the dystrophin gene. Even the micro version appeared able to reverse the muscle-wasting process, but it was not as effective as the full gene.

However, in the Sept. 16 paper, Chamberlain and colleagues describe how they developed A stripped-down vectors that did not raise a host immune response and which delivered the full-length, muscle-specific dystrophin gene. They showed that the full gene could be delivered to muscles of young and old mice, even well after severe muscle damage had developed. Also, they showed that normal muscle function was restored to a level that directly correlated with the amount of the gene that was delivered.

“These results are extremely encouraging. We have shown that replacing the dystrophin gene will correct this disease, even in older animals. In future research, we hope to develop better methods to deliver the gene to all the muscles of the body, as currently we are limited to treating relatively small muscles. We believe these results also support the need to move forward with human clinical trials to assess the safety of these methods in patients,” Chamberlain said.

The research was funded by grants from the National Institutes of Health, the Muscular Dystrophy Association and the Apex Foundation, a family foundation established by Bruce and Jolene McCaw. Other authors of the paper include Christiana DelloRusso, the lead author, of the UW Departments of Physiology and Neurology; Jeannine M. Scott, Dennis Hartigan-O’Connor and Robert W. Crawford of the Department of Neurology; former UW researchers Giovanni Salvatori, Catherine Barjot and Ann S. Robinson, and Susan V. Brooks of the University of Michigan.