The start of any new gene therapy trial is an exciting and nervous time. But for the participants and doctors involved in the recently launched trial for Duchenne Muscular Dystrophy (DMD) at Columbus Children's Hospital in Ohio, the long, hard road it took to get there makes it especially momentous.
Researchers discovered the gene for DMD 20 years ago but since it is one of the largest genes known, it was too big to work with. In 2000, geneticist Xiao Xiao found a way to miniaturize the gene. His team at the University of Pittsburgh then tested the mini gene in a strain of mice with muscular dystrophy. The improvement seen in the muscle tissue of the mice was dramatic, and led to the human trial that just began.
DMD patients lack the gene that controls production of a protein called dystrophin, which helps keep muscle cells intact. Patients with DMD usually die by the age of 25, often because of the failure of the heart and breathing muscles. In this trial, six boys will receive injections to deliver the mini-dystrophin gene to their biceps. Since the injections were limited to one muscle, dramatic results aren't expected. The trial is only designed to test the safety of the treatment.
And even if this trial proves to be safe, Xiao says there is a roadblock in the fact that the treatment currently requires multiple, direct injections into the muscles in order to deliver the gene.
"The limitation of that is the gene vehicle will not be widespread," he says. "It willŠ be localized around the injection site. However, diseases like muscular dystrophy affect almost every skeletal muscle cell. So you cannot, in theory, inject the genes into every muscle cell directly. So we have to figure out a novel or innovative way to deliver or disseminate [the gene]."
He made progress on that front in 2005, when he discovered a way to deliver the gene to muscles through the bloodstream. One common gene therapy technique is to take the harmful material out of a virus and use the remaining shell to deliver the gene. But most of the viruses used for this purpose have been too large to pass through the bloodstream.
Xiao tested a virus called AAV8 and filled it with a gene for a muscular dystrophy as well as a gene that causes cells to glow green in fluorescent light. When he injected the gene-filled AAV8 into the bloodstream of hamsters with muscular dystrophy, he saw that a single injection successfully reached every muscle in the hamsters, including the heart.
"The gene is basically expressed in every muscle cell," Xiao says. "The entire animal became green."
As Xiao reported in the journal Circulation, the procedure profoundly improved heart and muscle function in the hamsters and significantly prolonged the animals' lives.
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