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Scientists Find Basic Defect in Muscular Dystrophy; Step Toward Treatment

December 22, 1987

NEW YORK (AP) _ Scientists have discovered the chemical defect that triggers the most common and deadly form of muscular dystrophy, a landmark advance toward finding a treatment, researchers say.

They identified a protein that muscle cells normally make with instructions from a gene. Duchenne muscular dystrophy begins when production of the protein is sabotaged by a flaw in the gene, scientists say.

The protein discovery ″tells us exactly what it is that needs to be corrected in order to develop treatment for the disease,″ said Donald Wood of the Muscular Dystrophy Association, which helped finance the research.

″Now all the real excitement starts.″

The next step is to find out what the protein does, and the new work suggests it may help regulate muscle contraction.

Researchers also found that mice with a Duchenne-like genetic defect lack the protein but somehow avoid getting symptoms of the disease.

Close study of the mice may give clues for human therapy, said Louis Kunkel, associate investigator at the Howard Hughes Medical Institute at Children’s Hospital in Boston.

The mouse provides the first animal version of Duchenne, which can be used for testing therapies, said Kunkel, who led the new research.

He declined to speculate when a treatment might be found.

Duchenne muscular dystrophy, which almost exclusively afflicts boys, appears in about one in every 3,500 male births in the United States. It causes progressive weakness and wasting of voluntary muscles, confining patients to wheelchairs by age 12 and killing most in their early 20s.

No direct treatment is known, although therapies can extend survival and improve quality of life.

The new work is reported in the journals Cell and Nature by Kunkel, Eric Hoffman of Children’s Hospital in Boston and Harvard Medical School, Robert Brown of Massachusetts General Hospital in Boston, and C. Michael Knudson and Kevin Campbell of the University of Iowa.

Researchers dubbed the protein ″dystrophin.″

Finding the protein is a ″great feat,″ said Salvatore DiMauro, a muscular dystrophy researcher at Columbia University College of Physicians and Surgeons in New York.

Dystrophin was found in muscle triads, a key area for regulating muscle contraction. That is the first clue for the crucial question of what dystrophin does, said geneticist Ronald Worton of the Hospital for Sick Children in Toronto.

Once dystrophin’s role is known, Kunkel said, researchers can experiment with therapies to take its place or make its function unnecessary in Duchenne patients.

Wood, scientific director of the muscular dystrophy association, said scientists are ″in the midst of determining how the disease is affected by having either no protein or some abnormal version.″

″We know that some boys (with the disease) lack it, and some boys have an abnormal version,″ he said.

Kunkel’s team found that dystrophin was missing in the ″mdx″ mouse, which has a Duchenne-like genetic defect but fails to develop symptoms.

The mouse’s muscles do not develop a buildup of connective tissue that is seen in human Duchenne, researchers said. That buildup may hamper the human muscle’s ability to regenerate, ultimately robbing the muscle of enough fibers for normal function, researchers said.

With more study of differences in Duchenne between humans and the mouse, ″we may find a way of, in a sense, simulating what nature does in mice ... and maybe being able to alleviate the clinical course in humans,″ DiMauro said.

To find dystrophin, researchers used a mouse counterpart of the normal Duchenne gene to create two chunks of the protein it instructs cells to make.

When the chunks were injected into rabbits and sheep, the animals’ immune systems created antibodies, substances that act like chemical bloodhounds. Those antibodies could find and latch onto the chunks.

The antibodies were then used to search for the whole protein in muscle tissue. They revealed the protein in normal tissue from mice and humans, but not in tissue from two Duchenne patients.

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