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As an 8-year-old boy becomes the first U.S. gene therapy patient for muscular dystrophy, one of the researchers behind the therapy talks about the 20 years it took to get there, and what lies in the future. This ScienCentral News video has more.
The Long Road of Research
When 8 year-old Andrew Kilbarger of Lancaster, Ohio received three injections in his right arm, he became one of six boys participating in the first U.S. gene therapy trial for muscular dystrophy. Andrew has Duchenne Muscular Dystrophy (DMD). 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.
The start of any new gene therapy trial is an exciting time. But for the Muscular Dystrophy Association (which funded the trial), and the participants and doctors involved at Columbus Children's Hospital, this is a particularly exciting event because for this disease, it has been a long, hard road.
Researchers discovered the gene for dystrophin 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 tested the "mini-dystrophin" 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.
Diseased (left) and treated muscle tissue (right). image: Xiao Xiao
But Xiao says there is still a big roadblock. The treatment 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. It will… be localized around the injection site. However, diseases like muscular dystrophy affect almost every skeletal muscle cell," he says." 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.
"So the virus particle actually serves like a cargo [ship]," Xiao explains. "So when the virus contacts the cells, it will dump the gene, unload the cargo into the cell. Then the virus will fulfill its role and disappear."
Green glowing gene
But most of the viruses tested for this purpose have been too large to pass through the bloodstream. While testing different virus shells to see which would be most effective, Xiao came across one called AAV8 that showed widespread delivery after injection into the abdominal cavity. So he filled it with the gene for a different kind of muscular dystrophy called Limb-Girdle Muscular Dystrophy (LGMD), and paired that gene with one that causes cells to glow green in fluorescent light, "So if that gene is functional in the muscle cell, a green fluorescent protein will be made," he says.
When they injected the gene-filled AAV8 into the bloodstream of hamsters with LGMD, they 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."
Most recently Xiao reported in the journal Circulation that the procedure profoundly improved heart and muscle function in the hamsters and significantly prolonged the animals' lives.
Unfortunately Andrew Kilbarger won't have such dramatic results. The trial is only designed to prove the treatment is safe, so researchers injected the gene directly into one of his biceps. If analysis of muscle tissue near the injection site shows telltale signs of improvement, and if Andrew and the other participants all appear as healthy as when the trial started, Xiao and his colleagues can move on to a larger trial.