MDA TEAM CORRECTS MUSCULAR DYSTROPHY
DEFECTS IN HAMSTER MUSCLES
TUCSON, Ariz., May 21, 1998 -- Genes for a muscle protein can, when injected into leg muscles in hamsters, correct defects in one form of muscular dystrophy, the Muscular Dystrophy Association (MDA) announced today. This finding regarding delta-sarcoglycan has important implications for treating human muscular dystrophies, researchers say.
"We're buoyed by this advance," said Dr. Leon I. Charash, chairman of MDA's Medical Advisory Committee. "It underscores the interdependency of proteins within healthy muscle, and shows the huge health benefit that may be realized by restoring the function of just one defective protein in muscular dystrophy."
It also provides an important new option for gene therapy, Charash added, "The sarcoglycan protein may be delivered virally without immunosuppressive drugs and still be well tolerated by the immune system. This is vitally important, because immune response has been one of the biggest hurdles for gene therapy for inherited diseases."
The form of muscular dystrophy in these experimental animals is limb-girdle muscular dystrophy (LGMD). In humans, the disorder causes progressive muscle wasting and weakness, starting in the muscles of the shoulders or pelvic area and moving to other muscle groups. Severe disability often results.
There are several genes that, when flawed, cause LGMD. Four of these are genes for muscle-cell membrane proteins called alpha-, beta-, gamma- and delta-sarcoglycan. These proteins are next to each other and are imbedded in the muscle membrane. Flaws in the genes for any of the four sarcoglycans result in partial or complete loss of a sarcoglycan protein, malfunction of the membrane and subsequent muscle degeneration. Research suggests a "leaky" muscle membrane is a cause of the problem.
MDA grantee Kevin Campbell of the University of Iowa led the research team, which published its findings in the May issue of Molecular Cell. Campbell is a Howard Hughes Medical Institute investigator and a member of MDA's Scientific Advisory Committee.
The researchers used a viral "shuttle" to deliver the delta-sarcoglycan genes to muscle tissue. They first inserted the genes into genetically modified adenoviruses and then injected the constructs into the hamsters' leg muscles.
All aspects of the injected muscles returned to normal, including the correct assembly of all proteins at the muscle-cell membranes and restoration of membrane function. The researchers consider this a crucial finding, because the loss of any sarcoglycan protein affects other proteins that assemble with it and, until now, it wasn't clear that restoration of one sarcoglycan by gene therapy would also restore the rest of the proteins to their normal positions.
"Our work clearly demonstrates the feasibility of adenoviral gene therapy for the treatment of limb-girdle muscular dystrophy," Campbell said. "It will serve as the foundation for future studies in sarcoglycan gene therapy. The relatively small size of the sarcoglycan genes is particularly attractive because they can be easily incorporated into an adenovirus or another virus."
Campbell also noted that there was no immune-system rejection of the inserted genes, the proteins made from them, or the viruses used to insert them, a problem that has plagued previous gene therapy experiments that used other genes. The new genes were still functioning more than six months after they were injected.
A possible explanation for the immune system's tolerance of the delta-sarcoglycan protein may be that it closely resembled another sarcoglycan that was still being produced by the animals. Humans with a sarcoglycan deficiency likewise produce the other sarcoglycans.
"The possibility of long-term sarcoglycan production without the need for immunosuppressive drugs would be a tremendous advantage," Campbell said. "We expect that our results will encourage researchers to more actively explore the use of sarcoglycan gene replacement for the treatment of limb-girdle muscular dystrophy."
MDA is the nonprofit health agency dedicated to curing muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and 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. The Association's programs are funded almost entirely by individual private contributors.
MDA's research program emphasizes development of gene therapy as a potential treatment for muscular dystrophies and related disorders and is now supporting several projects in this area.
The first human trials of gene therapy for muscular dystrophy are slated for this fall, when MDA funding will enable researchers from Ohio State University and the University of Michigan to test the safety aspects of gene insertion to correct Duchenne muscular dystrophy, a childhood-onset muscular dystrophy that is uniformly fatal by early adulthood.
Today's findings will likely shorten the time to human trials of gene therapy for LGMD and bode well for all four sarcoglycan-related forms of LGMD.
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