Spotlight on Research for 2002

November 2002 (historical)

Mouse Muscles Restored Through Vector Gene Delivery

Scientists have discovered how to reverse muscle degeneration in a mouse model of Duchenne muscular dystrophy, a genetic disorder in which muscle cells become progressively more damaged and die. Researchers at the University of Washington, Seattle, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), along with researchers at the University of Michigan, Ann Arbor, supported by the National Institute on Aging, have devised a way to revitalize wasting muscle by using a special carrier to introduce the missing dystrophin gene into the diseased muscle tissue. Dystrophin is required to maintain muscle.

Using a strain of mouse that lacks the dystrophin gene, Jeffrey S. Chamberlain, Ph.D., in Seattle, and Susan V. Brooks, Ph.D., in Ann Arbor, and their colleagues injected affected muscles with the missing gene, using a special adenovirus vector, or carrier. The muscles became more able to resist injury and muscle function was restored. The finding could eventually lead to gene therapies for patients with Duchenne muscular dystrophy.

The key to the study's success was the modified adenovirus vector. Previous attempts to inject an adenovirus with an abbreviated form of the dystrophin gene produced promising results, but the shortened form of the gene was not as effective as the full-length gene. Also, while the delivered gene improved the muscle tissue in very young mice and adult mice with compromised immune systems, adult mice with healthy immune systems developed an immune response to the vector, and their muscles eliminated the gene after 10 to 20 days. The group decided to modify the adenovirus vector. They stripped it of viral components that might cause the immune response they wanted to avoid, making more room for the very large dystrophin gene. They added the entire gene to the adenovirus and tried again. The full gene in the modified adenovirus reversed the muscle wasting process more effectively than the shortened form of the gene, without causing an immune response.

"This breakthrough shows that it's possible to reverse the terrible muscle wasting characteristic of Duchenne muscular dystrophy,"says Stephen I. Katz, M.D., Ph.D., NIAMS director. "The researchers' successful use of a modified adenovirus as the vector for gene delivery into muscle will no doubt stimulate more promising research on gene therapy for the muscular dystrophies and other diseases as well."

There are still obstacles to overcome, says Dr. Chamberlain. "Chief among these are the need for a method to deliver these vectors to muscles all over the body, and better methods to produce these vectors in large quantities."

People with Duchenne muscular dystrophy are usually male, and the disease is diagnosed in early childhood. The muscles waste away until they can no longer support the body or its organs, and the patient dies, usually from respiratory weakness or heart failure, before age 25.

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DelloRusso C, Scott JM, Hartigan-O'Connor D, Salvatori G, Barjot C, Robinson AS, Crawford RW, Brooks SV, Chamberlain JS. Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin. PNAS 2002;99(20):12979-12984.