Gene therapy strengthens monkeys’ muscles, may eventually work for human diseases

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Injecting a gene into thigh muscles of a monkey’s leg greatly increased muscle mass and strength, a finding that could have potential application in a variety of human diseases that involve muscular weakening, researchers reported this week in the new journal Science Translational Medicine. The effects have now persisted for as long as 15 months and no side effects have been apparent, according to the researchers from Ohio. Clinical trials in humans are expected to begin next year.

Researchers have long sought ways to boost muscle mass and tone. Androgen steroids and glucocorticosteroids are the most obvious approach, but both have long-term consequences that render them less than desirable. Many researchers have thus turned to gene therapy, but results have been mixed so far.

Physiologist H. Lee Sweeney of the University of Pennsylvania has been working with a gene that is the blueprint for a protein called insulin-like growth factor 1, or IGF-1. Sweeney injected the gene for IGF-1 into one back leg of rats and found that the muscles in that leg became as much as 30% bigger than those in the untreated leg, even without exercise. But Sweeney has since switched his studies to focus on a chemical called follistatin, which promises to be more useful.

Work on that chemical was pioneered by molecular biologist Se-Jin Lee of Johns Hopkins University, who had been studying another chemical called myostatin. Muscles in young animals continue to grow until they reach maturity, at which time the body begins producing myostatin, which blocks the growth process. Researchers have been looking for chemicals that would block the activity of myostatin, thus allowing the muscles to continue their growth. Lee discovered another naturally occurring chemical called follistatin that is the strongest blocker of myostatin activity known. Lee found that giving follistatin to mice caused them to bulk up substantially. Genetically engineering mice to produce extra amounts of follistatin and to not produce myostatin led to exceptionally muscular mice whose muscle fibers were more than double the size of normal mouse muscle fibers.

In the new study, Dr. Jerry R. Mendell, director of the gene therapy center at Nationwide Children’s Hospital in Columbus, Ohio, and his colleagues inserted the gene for follistatin into a defanged cold virus, which they used to insert the gene into thigh muscles in the legs of healthy macaque monkeys. Eight weeks after the treatment, the monkeys’ leg muscles were 15% bigger and as much as 78% stronger. The effects persisted for the full 15 months that the monkeys were studied and no obvious side effects were observed.

The treatment would not cure muscle diseases such as muscular dystrophy or amyotrophic lateral sclerosis, which are caused by genetic defects, Mendell said. But it could strengthen the weakened muscles, allowing victims of those disorders to use them for longer periods.

The results in the monkeys should be sufficient to persuade the Food and Drug Administration to allow clinical trials of the technique in humans, Mendell said. He hopes to begin such studies by the middle of next year. The first patients will be people with inclusion body myositis, a rare condition that weakens the muscles of adults over the age of 50.

Mendell conceded that the therapy could be abused by athletes seeking to improve their muscle strength. But he noted that, if it is approved eventually, it will be closely regulated and will likely be very expensive. Athletes, he said, are more likely to stick to cheaper and more readily available steroids.

-- Thomas H. Maugh II

Associated Press