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Obstacles in Muscular Dystrophy Therapy Overcome

Swiss study says new genetic technique works in mice

WEDNESDAY, Sept. 19, 2001 (HealthDayNews) -- A new technique that overcomes some major barriers in the effort to develop a gene therapy for muscular dystrophy has worked well in mice, Swiss researchers report.

In muscular dystrophy, muscle cells wither and die because some of their proteins are produced in mutated forms that cannot maintain the structural integrity of the cells. The new treatment uses a small section of a foreign protein to hold the cells together, reports a research team led by Markus A. Ruegg, associate professor of neurobiology at the University of Basel, in the Sept. 20 issue of Nature.

The idea is "not to bring the molecule back that is causing the disease but to replace it by a molecule that is either homologous or functionally similar," says Ruegg. Other research teams have tried the approach with other proteins, but the Swiss work is different because it uses only a small segment of one protein, just enough to hold the cellular scaffold together.

Just as important, the mini-protein is secreted from the muscle fibers where it is made and can reach neighboring fibers, Ruegg says. A major problem in other gene-therapy research has been getting the repair gene into enough muscle cells to make a difference, he says.

Another problem is that most gene therapy efforts have worked with very large proteins that are hard to fit into a virus that would carry them into cells. Also, the proteins can arouse an immune response that makes the body attack the cells that carry them.

The new treatment uses a gene for a segment of a protein called agrin. "Both problems should not be a major issue when the miniaturized agrin is used," Ruegg says.

"This is great news," says Xiao Xiao, assistant professor of molecular genetics and biochemistry at the University of Pittsburgh, who also is involved in gene-therapy research for muscular dystrophy. "If you can insert this protein, you can rescue neighboring cells."

But it's a long way from the laboratory to treatment of human patients, Ruegg says. "Gene therapy in general has many obstacles to overcome. These include immune rejection of transduced cells [which can also be caused by the viruses used in gene therapy], the need for appropriate and tissue-specific control of expression, the requirement for systemic spread and the lack of efficiency and accuracy of gene delivery," he says.

Muscular dystrophy actually is a family of diseases. The mice in the Swiss study were bred to have the most common form of congenital muscular dystrophy in Europe. But Ruegg says the method used in his laboratory "is not restricted to congenital muscular dystrophy or muscular dystrophies in general." Ruegg is on the management team of a start-up company, MyoContract Pharmaceuticals research, "that aims to develop drugs for the treatment of neuromuscular disease."

Xiao says the Swiss technique is potentially applicable to Duchenne muscular dystrophy, the most common kind in the United States. American researchers have tried a similar approach, using a form of dystrophin, the protein that is mutated or deleted in Duchenne muscular dystrophy. But because dystrophin is found within cells, the defect must be corrected cell by cell.

If the Swiss approach can be made to work in humans, many cells could be saved with a single treatment, Xiao says. "This is totally new," he says.

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Ruegg says with so many questions to be answered, "the success of this concept must be shown for other cases. Clinical applications are certainly many years down the road."

For information about the different forms of muscular dystrophy and efforts at gene therapy, go to the Muscular Dystrophy Association or the Parent Project.

SOURCES: Interviews with Markus A. Ruegg, Ph.D., associate professor of neurobiology, University of Basel, Switzerland, and Xiao Xiao, Ph.D., assistant professor of molecular genetics and biochemistry, University of Pittsburgh; Sept. 20, 2001, Nature
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