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NIH-Funded Gene Therapy Restores Muscle in Aging Mice

By Cori Vanchieri

Muscles do more than help weight lifters and marathon runners win trophies. We count on them for the more mundane tasks of standing up, moving across the bathroom floor, and lifting grocery bags. Many of us take for granted how our muscles sustain us until we begin to age and those supportive fibers wither.

"As they go past ages 50 or 60, people begin losing their strength and muscle mass," explained Dr. Richard W. Lymn, director of the Muscle Biology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Muscle strength decreases up to one-third in humans between ages 30 and 80. The risk for falls increases, and with less muscle cushioning the vertebrae and the hip area, the impact of a fall is taken much more directly by the bones.

NIH-supported researchers are using gene therapy to help the body fight the seemingly inevitable effects of aging or to give it a hand in repairing the damage caused by injury or muscle-wasting disorders like muscular dystrophy. Using a virus to carry a growth-promoting gene directly to muscle fibers, the scientists were able to prevent in mice the age-related decrease of muscle size and strength that leads to unsteadiness and impaired mobility. Their study (PNAS 1998;95:15603-15607) was funded by NIAMS, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Muscular Dystrophy Association.

Normally, when muscle is damaged, satellite cells within the muscle are activated to do their repair work by insulin-like growth factor-1 (IGF-1) and other signaling proteins. In elderly humans and animals, the ability of muscle to activate satellite cells to repair muscle mass diminishes. In the case of muscular dystrophy, muscle damage occurs at such a high rate that the body's intrinsic repair system can't keep up.

"I felt the simplest way to do something about the weakened repair system was to put back into the muscle a chronic signal that would keep the satellite cells activated to be more responsive and repair damage more completely," said Dr. H. Lee Sweeney, the study's leader and professor of physiology at the University of Pennsylvania School of Medicine.

In the experiment by Sweeney's team and researchers at Massachusetts General Hospital, each mouse served as its own control. The virus was injected into one leg, while the other was left untouched for comparison. The injections were tested in mice that were 2 months, 18 months, and 24 months old — the equivalents of adolescent, 55-year-old, and 70-year-old humans.

After several months, the adolescent mice showed a 15 percent increase in muscle mass in the injected legs compared to the control legs. Both groups of older mice experienced a 19 percent increase in muscle mass. The injection completely prevented the normal decrease of muscle mass associated with aging. Even better, according to the researchers, was the 27 percent boost in muscle strength experienced by the older mice and the preservation of the fastest muscle fiber types. Both mass and function were restored to their youthful levels.

Muscle regeneration continued until it reached a steady state. The muscles did not become overly bulky, as they would with steroid use. And no degeneration occurred up until the mice's death.

An Effective Virus

Researchers started with an adeno-associated virus, or AAV, which is adept at introducing its genetic material into the cells it infects. They stripped the AAV of its own genetic material and replaced it with a naturally occurring gene for IGF-1. They also inserted a "promoter" to drive production of the growth factor. This re-engineered virus was then injected into the muscles of the mice.

The promoter they chose, the myosin light chain promoter, is specific to muscle tissue so that IGF-1 production would be limited to the muscle. The researchers did not want any IGF-1 that may have accidentally leaked outside of the muscle to proliferate and stimulate growth of other organs.

"The research team was asking two main questions: Can we develop a vector — in this case, a virus — that can be used to specifically deliver genetic material to skeletal muscle or have the genetic material expressed solely in skeletal muscle? And, can we do it in such a way that the expression will have a positive effect and no noticeable or serious negative effect?" Lymn said. "They've shown they can do both."

While the method of delivery is similar to other forms of gene therapy, the aim is somewhat different. "What you're doing here is increasing production of a substance that has been appearing in the cells all along," explained Lymn. "Much gene therapy is aimed at repairing a defective protein or fighting an invading organism."

NIAMS supported this work with a grant to develop mechanisms of gene therapy for Duchenne's muscular dystrophy. But it's turned out to have somewhat different applications.

"In the worst sorts of muscular dystrophy, like Duchenne's muscular dystrophy, damage is so severe that satellite cells are eventually depleted," Sweeney said. Without satellite cells, IGF-1 is not effective. Experiments with a Duchenne's mouse model are bearing that out, he said. Sweeney has higher hopes for Becker's muscular dystrophy, in which the rate of damage is slower. "If we build greater muscle mass and boost the satellite cells, we may be able to stabilize the condition." His group began testing a transgenic mouse model of Becker's muscular dystrophy in January.

Sweeney expects to complete animal safety testing this summer and then request FDA approval to do a phase I clinical trial in patients with Becker's muscular dystrophy. "If we can show both efficacy as well as safety in humans, it will open the way to trials in other human conditions, including aging and amyotrophic lateral sclerosis (ALS)." ALS, also known as Lou Gehrig's disease, is a neuromuscular disease that causes muscle wasting.

Meanwhile, Lymn sees potential for this therapy in other arenas. "When muscle is damaged severely, in the case of a bad burn, regeneration can be very incomplete. This therapy may help in forming a more normal looking and functioning muscle." It may also work for bad muscle tears that result from sports injuries.

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