Gene therapy reaches muscles throughout the body and reverses muscular dystrophy in animal model

The gene therapy was able to perform in all muscles in the mouse, and would not necessarily have to carry the dystrophy gene

Researchers have found a delivery method for gene therapy that reaches all the voluntary muscles of a mouse – including heart, diaphragm and limbs – and reverses the process of muscle-wasting found in muscular dystrophy.

“We have a clear ’proof of principle’ that it is possible to deliver new genes body-wide to all the striated muscles of an adult animal. Finding a delivery method for the whole body has been a major obstacle limiting the development of gene therapy for the muscular dystrophies. Our new work identifies for the first time a method where a new dystrophin gene can be delivered, using a safe and simple method, to all of the affected muscles of a mouse with muscular dystrophy,” said Dr. Jeffrey S. Chamberlain, professor of neurology and director of the Muscular Dystrophy Cooperative Research Center at the University of Washington School of Medicine in Seattle. He also has joint appointments in the departments of medicine and biochemistry.

Chamberlain is the senior author of the paper describing the results, which will be published in the August edition of Nature Medicine. The paper describes a type of viral vector, a specific type of an adeno-associated virus (AAV), which is able to ’home-in’ on muscle cells and does not trigger an immune system response. The delivery system also includes use of a growth factor, VEGF, that appears to increase penetration into muscles of the gene therapy agent. Chamberlain said the formula was the result of about a year of trying different methods.

Duchenne muscular dystrophy is an X-linked genetic disorder that strikes one of every 3,500 newborn boys. The genetic disorder eliminates production of 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.

“By giving one single injection of this AAV vector carrying a mini-dystrophin gene into the bloodstream, we are able to deliver therapeutic levels of dystrophin to every skeletal and cardiac muscle of an adult, dystrophic mouse,” Chamberlain said. “These muscles include the heart, the muscles used during breathing, and all the limb muscles. The mice show a whole body effect, with a dramatic improvement of their dystrophy.”

The findings hint that it may be possible someday to introduce other genes into adult muscle to address conditions besides muscular dystrophy. The gene therapy developed at the UW was able to perform in all muscles in the mouse, and would not necessarily have to carry the dystrophy gene. Muscle represents about 40 percent of the human body, and there are a number of ailments that involve muscle. Gene therapy could someday reinforce muscles weakened by cancer or normal aging, or treat cardiac disease. But Chamberlain stressed that the paper represents one discovery on the long path to any clinical applications in people.

The results involved mice, so researchers do not know if the method will work in larger animals or people. Chamberlain and colleagues in the Muscular Dystrophy Cooperative Research Center are gathering data to seek regulatory approval for a limited trial in humans to determine the safety of a very small amount of the vector in human muscle. If the experiments take place — and if results are encouraging — researchers would continue to test the method in larger animals and hopefully eventually humans. But Chamberlain stressed that there are a number of scientific challenges and regulatory requirements along the way, so any tests on humans are many years in the future.