Duke Researchers Develop First Treatment For Rare Muscle Disease

February 14, 1998

DURHAM, N.C. -- Researchers at Duke University Medical Center have demonstrated for the first time that it is possible to regenerate functional muscle in a rare type of muscular dystrophy.

Based on their successful tests in animals, they have been working closely with the federal Food and Drug Administration to begin using the treatment in children with a fatal muscle-wasting condition called Pompe disease.

The injectable enzyme treatment was developed by Duke pediatric medical geneticist Dr. Yuan-Tsong Chen. He said it is the first therapy to show promise in any type of a genetic muscle-wasting disease.

Muscular dystrophy is a broad category of inherited diseases in which the body's muscles don't function normally. Usually, an important muscle protein is missing or defective. Many doctors have been unsure if it is even possible to regenerate muscle tissue that has been damaged in these muscle-wasting diseases. Chen has now shown it is possible in principle to replace a missing component of muscle and improve muscle strength.

"This is a major milestone is our long-term efforts to develop an effective treatment for this devastating fatal disease," Chen said. The scientists reported their findings in the Feb. 15 issue of the Journal of Clinical Investigation. The research was supported by grants from Synpac Pharmaceuticals Ltd., the Japan Health Science Foundation and the Muscular Dystrophy Association.

Within this year, Chen and his colleagues expect to treat children born with the rare and always fatal Pompe disease, which is caused by an inherited defect that results in a deficiency in an essential enzyme called acid alpha glucosidase (GAA).

Normally the GAA enzyme helps the body break down stored glycogen into glucose, a sugar the body uses for energy. Without the active enzyme, stored glycogen builds up in the body's muscles, eventually destroying them. About 100 children are born with Pompe disease each year in the United States. In a severe form, the disease is always fatal, usually within the first two years of life.

Chen and Duke colleagues Helen Wen Yang, Mark Pennybacker, and Johan L.K. Van Hove had been searching for an effective treatment for Pompe disease for several years. The treatment they developed is similar to that used to treat children with the "bubble boy" disease, a deficiency in the enzyme adenine deaminase (ADA). In each case, the first available treatment was injecting a missing enzyme into the bloodstream.

"But for Pompe disease, previous attempts at enzyme replacement therapy failed because the enzyme was not taken up by the muscle cells," Chen said. "We circumvented this problem by using the body's own system to get the enzyme inside muscle cells."

Chen solved the problem by purifying a form of the enzyme that has a modified residue attached to the sugar molecule of the enzyme. The modified molecule is recognized by special muscle cell receptors, which then trigger the cell to engulf the enzyme and direct it to where it is needed.

The researchers used molecular biology techniques to insert the human gene for GAA into a common type of cell grown in the laboratory. These cells act like a mini-factory, churning out human GAA enzyme. After several years of experimentation, Chen and his colleagues obtained enough purified enzyme to begin tests on laboratory animals.

Chen collaborated with Tateki Kikuchi and Nobutsune Ichihara of the National Institute of Neuroscience, Tokyo, and Makoto Mizutani of the Nippon Institute for Biological Science, Kobuchizawa, Japan, who developed a strain of Japanese quail also missing GAA. These birds can't fly and when turned on their backs can't right themselves.

The team of researchers used three test groups of birds. Two birds were injected with a high dose of purified human GAA, two with a low dose of GAA, and two were injected with salt solution. Each bird received seven injections over a 16-day period. Two days after the last injections, the scientists evaluated the birds' ability to right themselves.

The high-dose GAA treatment improved muscle strength so much that both birds could right themselves when flipped on their backs. One bird could even fly a short distance. Tests showed these birds had an increase in GAA activity and decreased muscle glycogen and improved muscle structure. The low-dose birds showed similar improvements, but to a lesser degree.

Because quail GAA and its human counterpart are not identical, researchers expected that the human form of the enzyme would not be as effective in quail. Laboratory tests revealed that quail muscle requires a higher dose of human GAA to restore active enzyme levels to normal.

"Based on these results, we believe this enzyme is a promising therapy for the human form of Pompe disease," Chen said. He said he will initially attempt to treat only a small number of children. "If it is successful, children will need a supply of the enzyme for their whole lives," he said.

Synpac Inc. of Middlesex, England, will supply the enzyme for the clinical trial.

Chen, one of a handful of experts in Pompe disease worldwide, confirms diagnosis on children born with Pompe disease in the United States.

He and his colleague Andy Amalfitano are also developing a gene therapy strategy for treating Pompe disease. They hope to inject a working copy of the gene into muscle cells using a modified virus to carry the gene into cells. If successful, a gene therapy strategy would allow the muscle to generate its own enzyme and eliminate the need for lifetime injections of the enzyme.

"We are hopeful that eventually we will be able to provide a child born with Pompe disease several options for treatment, and even a cure, within our lifetime," Chen said.
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Duke University Medical Center

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