EDITORS: Copies of the color slide shown in this release are available on request.
BALTIMORE---University of Michigan scientists have developed a viral vector which delivers the gene for dystrophin, a protein critical for normal maintenance of muscle tissue, to the muscles of adult mice with muscular dystrophy.
The secret: An ordinary virus with all its natural genetic material removed to make room for the dystrophin gene which triggers production of the protein. The result: Dystrophic mice with muscles producing high levels of normal dystrophin protein for several months.
"We have induced long-term expression of the full-sized dystrophin protein for at least three months in the muscles of adult mice with Duchenne muscular dystrophy," said Jeffrey S. Chamberlain, associate professor of human genetics in the U-M Medical School. "We have shown that mice can incorporate the gene from our viral vector into their muscle tissue. It is an encouraging result, but it is not a cure."
Chamberlain presented recent results from ongoing U-M research to develop an effective gene therapy for muscular dystrophy at the American Society for Human Genetics Meeting held here this week.
Duchenne muscular dystrophy is a common genetic disease occurring in one out of every 3,500 males. Muscular dystrophy is caused by mutations in a large, complex gene which produces dystrophin---a protein critical for normal maintenance of muscle tissue. The dystrophin gene is the largest ever identified, which greatly complicates researcher's efforts to develop an effective gene therapy for the disease. The severity of symptoms correlates with the degree to which expression of dystrophin is impaired. Without dystrophin, children with muscular dystrophy gradually lose muscle tissue and eventually die by their mid-20s of heart or respiratory failure.
For seven years, Chamberlain and his U-M colleagues have been confronting the daunting technical obstacles to an effective gene therapy treatment for muscular dystrophy and finding ways to overcome them. Recent work has focused on developing modified adenoviruses---the same type of virus that causes colds. Since adenoviruses have a natural ability to enter muscle cells, they make excellent vectors or delivery vehicles for the dystrophin gene.
"Unfortunately, dystrophin is too large to fit into a conventional adenovirus," Chamberlain said. "Another problem is finding a way to avoid triggering the body's natural immune response, so it won't kill muscle cells that take up the dystrophin virus."
Chamberlain calls his solution a "gutted virus." Stripping away genes normally found in the virus not only frees up enough space for a full-sized version of dystrophin, it also may make it possible to avoid triggering the body's immune system, according to Chamberlain.
So far, Chamberlain has only tested the virus in an immuno-deficient strain of dystrophic mice. This allowed him to see if the vector was stable, without worrying about immune response.
"The results suggest these new gutted viruses are very stable in adult animals, and that they can effectively deliver full-sized dystrophin to adult, dystrophic animals for extended periods of time," Chamberlain said. "Now that we have succeeded at producing long-term expression of dystrophin in adult mice without a working immune system, the next step is to test the virus in mice with a normal immune response.
"If our adenoviral vector is able to produce this same level of dystrophin expression in immunologically normal mice, then we may be in a position to begin limited clinical trials for safety in humans."
Collaborators in U-M research to develop a new viral vector for gene therapy for muscular dystrophy include research fellows Catherine Barjot, David Calnek, Michael Hauser and Giovanni Salvatori.
The work is funded by the National Institutes of Health, the Muscular Dystrophy Association and a private foundation established by a Birmingham, Mich. couple, Chip and Betsy Erwin, to support the U-M research program.
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