The University Record, November 9, 1998
By Sally Pobojewski
Health System Public Relations
U-M scientists have developed a new generation of gutted viral vectors that deliver the gene for dystrophin to the muscles of adult mice with muscular dystrophy without triggering their immune systems to attack the foreign virus. The vector is called a gutted virus because it has been stripped of most of its original genes to make room for the large dystrophin gene.
Dystrophin is a protein critical for normal maintenance of muscle tissue. Muscular dystrophy is caused by mutations in a large, complex gene which contains instructions telling muscle cells how to produce dystrophin. Because they lack the genetic code to produce dystrophin, children with muscular dystrophy gradually lose muscle tissue and die of heart or respiratory failure.
At last years American Society for Human Genetics meeting, Jeffrey S. Chamberlain, associate professor of human genetics, reported the viral vectors ability to induce long-term expression of the full-sized dystrophin protein in an immuno-deficient strain of adult mice with Duchenne muscular dystrophy. At this years meeting, Giovanni Salvatori, post-doctoral research fellow in Chamberlains lab, reported the same results in mice with a normal immune system.
Using this new version of our viral vector, we have induced stable production of dystrophin for at least four months in muscle fibers of adult, dystrophic mice with normal immune systems, Salvatori said. Removing a reporter gene called LacZ from the vector was the key to reducing the vectors strong immunogenic effect. Although we still see a small immune response, it peaks after 30 days and does not appear to adversely affect the ability of mouse muscle to take up the vector and produce dystrophin.
A new cell packaging line, also under development at the U-M, will make it possible to produce large amounts of the vector without contamination by other proteins or viruses that could trigger an immune response in humans, according to Salvatori.
The result is significant because stability and immune response were two major problems that remained to be solved in mice before the U-Ms dystrophin vector could be tested for safety and effectiveness in humans. Chamberlain and Jerry Mendel of the Ohio State University Medical Center plan to begin testing the vector for safety in humans in the spring.
Chamberlain and his research team have been overcoming technical obstacles to an effective gene therapy treatment for muscular dystrophy for eight years. They have focused on using modified adenovirusesthe same type of virus that causes coldsas delivery vehicles, because they have a natural ability to enter muscle cells and deliver the dystrophin gene. Chamberlain is a member of the Department of Human Genetics and is affiliated with the Center for Gene Therapy in the Health System.
Current collaborators in the program include Ph.D. research fellows Catherine Barjot, Catherine Begy, Christiana DelloRusso, Dennis Hartigan-OConnor, Ann Saulino and Michael Hauser, who is now at Duke University.
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.