Researchers from Nationwide Children’s Hospital have identified a potential new treatment for the most serious form of muscular dystrophy. The study, which appeared in Molecular Therapy, found that gene therapy improved muscle strength and stability in a mouse model of Duchenne muscular dystrophy, the most common form of the group of inherited muscle disorders.
A fatal, fast-moving degenerative disease, Duchenne Muscular Dystrophy—or DMD—affects one in 5,000 newborn males. Children with DMD may lose the ability to walk by mid-teens, and death from cardiac and respiratory complications usually occurs between 20 and 30.
A defective gene for dystrophin—a protein in the muscles—causes the disease. DMD patients don’t produce dystrophin, and genetic researchers have struggled to replace the protein—one of the longest human genes—because of its large size and immune issues. As a result, Nationwide Children’s researchers tested an alternative approach, using a different protein called Alpha 7 Integrin, which also helps stabilize muscle, as a replacement for the missing dystrophin.
“We were looking for a protein that was smaller and already expressed in patients. Therefore patients would already be tolerant to the protein,” says Louise R. Rodino-Klapac, PhD, the co-lead study author with Jerry R. Mendell, MD, director, Center for Gene Therapy in The Research Institute at Nationwide Children’s.
Researchers delivered the human Alpha 7 Integrin gene in adolescent mice with muscular dystrophy using a virus called AAV (adeno-associated virus) as a delivery system. AAV is a small virus that has never been associated with any human disease. Tests showed that Alpha 7 slowed the normal progression of the disease in limbs that were injected with the protein.
“When you repetitively damaged the muscle, the muscle retained its force like it would in a normal mouse,” says Kristin N. Heller, an Ohio State University doctoral student in Molecular, Cellular and Developmental biology and a co-author of the study.
The Nationwide Children’s study focused on just DMD, but researchers say their approach might have broader application. “It has the potential to be a more universal therapy and apply to other forms of muscular dystrophy,” Rodino-Klapac says. Further research needs to determine those links, she says.
Clinical trials aren’t imminent, but researchers say their approach using Alpha 7 gene therapy (using the protein to fill the gap left by the missing dystrophin) could be more effective than the only current DMD treatment, corticosteroids, which have modest effect. What’s more, the new method also could be more convenient. “We are hopeful it would be a one-time treatment,” Rodino-Klapac says. “That is the advantage of gene therapy. Using AAV, it should be stable for a long period of time.”
Alpha 7 might not cure the disease, but it could alter the natural history of it. “The first thing to change the natural history was steroids,” Rodino-Klapac says. “That enabled boys to walk a little bit longer. Potentially, Alpha 7 would extend this even longer and provide marked improvement in the quality of life of DMD boys”.
The study was funded by a Wellstone Muscular Dystrophy Cooperative Research Center grant at Nationwide Children’s and a Wellstone Muscular Dystrophy Cooperative Research Center Graduate Student Training Fellowship granted to Heller, an Ohio State doctoral student.
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