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Gene therapy for muscular dystrophy

University of Pennsylvania School of Medicine

In a study of Muscular Dystrophy, scientists at the University of Pennsylvania School of Medicine have found that a common delivery system used in treating the disease through gene therapy may trigger an immune response in mice unless it is used in combination with a muscle-specific promoter that localizes the expression of genetic material.

The study findings are published in the new issue of the journal Human Gene Therapy.

"Even when you use low-levels of a promoter that is not restricted to the afflicted area, you run the risk that you will immunize the patient against the very protein you are trying to get made," said H. Lee Sweeney, PhD, chairman of the Department of Physiology at Penn and lead author of the study. "This is relevant because some of the clinical trials that have been started are not using restricted promoters. The journal wanted to get this message out there."

In their published findings, the Penn researchers state that it is "crucial" to establish which method should be used before expanding clinical trials.

The scientists used two groups of mice that had been engineered to lack a protein called gamma sarcloc-glycan (gsg) in their muscles, which is the same protein that is missing in muscluar dystrophy (MD).

The researchers administered the protein to both groups of mice by enclosing the gsg in the recombinant adeno-associated virus (rAAV) - a commonly used vector that has been described in previous scientific research as non-immunogenic.

In one group of mice, the rAAV included a cytomegalovirus (CMV) promoter -- which will express the DNA material it carries in any tissue. The results Sweeney found: "Although we didn't see the immune response in the CMV promoter in a large percentage of the mice - we did see it."

In the second group of mice, when the rAAV that contained the gsg material was delivered under the control of the muscle creatine kinase promoter - which is muscle-specific -- there was no immune response.

"What we think happens is that if the virus gets into tissues that are very good at presenting foreign proteins to the immune system, then an immune response is generated to any proteins the virus may express," Sweeney said. "Skeletal muscle (which is affected by MD) is very bad at presenting - we've never seen an immune response, as long as the expressed protein is restricted to the skeletal muscle."

"The issue is: If you put DNA material into a virus that will fix the disease -will it also trigger an immune response?" Sweeney said.

"The answer appears to be - possibly. But as long as you keep the protein in the skeletal muscle and nowhere else, you don't get an immune response."


The study was funded by the National Institutes of Health, the Muscular Dystrophy Association and the Association Francaise contre les Myopathies.

Sweeney's collaborators in the research were: Laurence Cordier, PhD, of Penn's Department of Physiology; Andrew A. Hack, PhD, and Elizabeth M. McNally, PhD, both of the University of Chicago, and Guang-Ping Gao, PhD; Narendra Chirmule, PhD, and James M. Wilson, MD, PhD, of Penn's Institute for Human Gene Therapy.

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