MDA RESEARCHERS REVERSE MUSCULAR DYSTROPHY IN NEW MOUSE MODEL OF DISEASE;
CREATE SECOND MODEL TO TEST THERAPEUTICS, TOO
TUCSON, Ariz., Sept. 21, 1998 -- Two MDA-funded research teams have developed mice, each with a different form of limb-girdle muscular dystrophy, and one team successfully treated one of the muscle disorders by injecting missing genetic information using a modified virus as a transport vehicle, the Muscular Dystrophy Association announced today. The mice are expected to speed research progress toward therapeutics including gene therapy, the insertion of new genes, to treat human muscle disorders.
Longtime MDA research grantee Kevin Campbell, professor of physiology and biophysics and investigator of the Howard Hughes Medical Institute at the University of Iowa, led one team. MDA grantee Elizabeth McNally, assistant professor of medicine at the University of Chicago College of Medicine, led the other.
"In May, Campbell's team of MDA-funded investigators proved the injection of genes can correct limb-girdle muscular dystrophy and restore muscle function in hamsters. Now, just a few months later, they've created a mouse model and successfully treated limb-girdle muscular dystrophy a second time," said Dr. Leon I. Charash, chairman of MDA's Medical Advisory Committee.
"The two new models for limb-girdle muscular dystrophy we now have," added Charash, "will speed testing of potential therapeutics so the most promising can be rapidly advanced as candidates for human trials."
Charash notes that mice with Duchenne muscular dystrophy have existed for many years, and been crucial in the pursuit of therapeutics for Duchenne muscular dystrophy, which also affects tens of thousands of boys.
Similarly, he reports, the development of mice with a form of amyotrophic lateral sclerosis by MDA researcher Mark Gurney at Northwestern University a few years ago probably has done more to advance research seeking treatments and cures for ALS than any other single event in the field. Commonly known as Lou Gehrig's disease, ALS affects some 35,000 Americans.
The Campbell group developed mice missing a muscle protein known as alpha-sarcoglycan, one of the proteins that, when absent, leads to limb-girdle muscular dystrophy in humans. In limb-girdle muscular dystrophy, the muscles of the shoulder and pelvic girdle weaken first, and weakness and wasting may then progress and spread to other muscle groups. The disease can begin in childhood or adulthood and can shorten life span. Seven genes have so far been found to cause limb-girdle dystrophy when they're abnormal and lead to the loss of a key muscle protein.
Campbell's team corrected the muscle defects in the mice by inserting a gene for alpha-sarcoglycan. They used a gene therapy strategy similar to one planned for use in humans by MDA researchers in the near future. The gene was injected into the animals' leg muscles using a modified virus as a transport vehicle.
The group published its findings in today's issue of the Journal of Cell Biology. MDA grantee Rachelle Crosbie in the Department of Physiology and Biophysics at the University of Iowa was also on the team, as was MDA grantee Joshua Sanes, professor of neurobiology at Washington University School of Medicine in St. Louis.
"We're very excited about this new animal model of limb-girdle dystrophy," Campbell said. "We do have a hamster with another form of this disorder, but these mice are easier to work with, and their disease appears to very closely resemble the human one. They're a very valuable research tool for studying a cause of limb-girdle dystrophy and for the development of therapeutic strategies."
The McNally team developed mice missing a similar protein known as gamma-sarcoglycan. The absence of this protein, which normally lies near alpha-sarcoglycan in the membrane that surrounds each muscle cell, also leads to limb-girdle muscular dystrophy in mouse and man. McNally credits graduate student Andrew Hack in her laboratory with much of the work that led to this connection.
"We now have an excellent model in which to test therapies," McNally said, noting that gene therapy is already being tried in these mice.
The group published its findings in the Sept. 7 issue of the Journal of Cell Biology.
The forms of limb-girdle dystrophy that result from sarcoglycan deficiency are among the disorders selected for the first clinical trials of gene therapy in muscular dystrophy. MDA-supported researchers plan to begin these trials early next year. They're now waiting for approval by the Food and Drug Administration.
MDA is a voluntary health agency working to defeat 40 neuromuscular diseases through programs of worldwide research, comprehensive patient and community services, and far-reaching professional and public health education. Recognized by the American Medical Association with a Lifetime Achievement Award "for significant and lasting contributions to the health and welfare of humanity," MDA maintains 230 hospital-affiliated clinics that offer families the best in care for progressive neuromuscular diseases.
MDA annually funds some 400 scientific teams worldwide. These investigators have made significant advances toward cures for several muscle-wasting diseases. They've pioneered breakthroughs that may well lead to therapies for heart disease, cancer, AIDS, Alzheimer's, Parkinson's, Huntington's, and cystic fibrosis. For information about MDA research progress and/or referrals to MDA clinics, call 1-800-572-1717, or visit MDA's Web site at www.mda.org. MDA programs are funded almost entirely by individual private contributors.
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