TUCSON, Ariz., July 29, 1999 -- The Muscular Dystrophy Association today announced that gentamicin, one of a family of aminoglycoside antibiotics commonly used for bacterial infections, will be tested in a clinical trial involving a few patients with Duchenne muscular dystrophy. The pilot trial is expected to get underway by the end of this year, and all participants will have a confirmed genetic flaw known as a "premature stop codon." This genetic problem, which affects about 15 percent of all people with Duchenne, instructs the muscle cells of Duchenne patients to stop making dystrophin, a protein that when absent causes the muscle-wasting disease.
In laboratory studies done by MDA grantees at the University of Pennsylvania Medical Center in Philadelphia, gentamicin injections allowed mice with a disease that closely mimics the human form of Duchenne muscular dystrophy to start making dystrophin in all muscles examined, including the heart and diaphragm. Muscle function in these mdx mice, which have a premature stop codon, was improved and signs of the disease were reversed with the restoration of just 20 percent of normal dystrophin levels. In the same study, mdx mice with significantly lower levels of dystrophin expression still displayed a reduction in disease symptoms.
"We're buoyed by this novel application for gentamicin," said Dr. Leon Charash, chairman of MDA's Medical Advisory Committee. "It has the potential to help thousands of youngsters and young adults affected by Duchenne muscular dystrophy."
Premature stop codons instruct cells to stop making a protein prematurely, before its synthesis is complete. A protein that cells manufacture when a premature stop codon exists is usually too small to be useful and is quickly destroyed by the cell.
Charash added, "Since this type of genetic defect is present as a subgroup in other forms of neuromuscular disease and for many other inherited diseases, including colorectal cancer, ovarian cancer, cystic fibrosis, and neurofibromatosis, the findings ultimately may have broad application."
Dr. H. Lee Sweeney, chairman of the Department of Physiology at the University of Pennsylvania School of Medicine, was the lead investigator on the study to be posted Friday or Saturday at www.jci.org and scheduled to be published in the Aug. 15 issue of the Journal of Clinical Investigation. He said, "I look forward to collaborating with Dr. Jerry Mendell at Ohio State University on a pilot trial to determine if safe dosages of gentamicin can benefit people with Duchenne muscular dystrophy caused by premature stop codons."
Sweeney, an MDA-funded investigator involved with the Institute for Human Gene Therapy, added, "It's vital that clinicians avoid prescribing gentamicin for muscular dystrophy and other inherited diseases until trial data show dose-specific health benefit. The antibiotic can have toxic side effects including hearing loss and damage to kidneys.
"If results of our planned gentamicin trial for Duchenne muscular dystrophy are positive," Sweeney explained, "then, the application for the drug would represent only a small percentage of the Duchenne patient population. The vast majority do not have premature stop codons. It costs about $1,000 per person to completely analyze the dystrophin gene, and gentamicin only has the potential to help those with genes containing premature stop codons."
Nonetheless, getting cells to skip over a premature stop codon and to start making a needed protein would be a real breakthrough in treating certain genetic diseases, Sweeney said. He noted that the approach also has shown promise in laboratory tests using the cells of people with cystic fibrosis, a genetic disease of respiratory and digestive systems; that certain dosing regimens might reduce the risk of serious side effects; and that other aminoglycoside drugs could be tested if gentamicin proves too toxic.
In Duchenne muscular dystrophy, a genetic flaw on the X chromosome causes the protein known as dystrophin to be absent from the membrane that surrounds each muscle cell, leaving the cells vulnerable to damage because their membranes are weak and easily torn under the stress of muscle contractions.
Because the gene for dystrophin is on the X chromosome, the disorder affects boys almost exclusively (girls being protected by a second, usually normal, X chromosome).
Beginning at birth, the muscles of children with Duchenne dystrophy are slowly destroyed by a lack of dystrophin and leaky muscle-cell membranes. Children usually start falling excessively in the early school years, lose the ability to walk by about age 10, and usually die in their 20s. Respiratory and cardiac muscles, as well as skeletal muscles, are affected.
The mdx mice that received gentamicin injections made dystrophin, and did better on tests of muscle function, as well as on tests that reflect muscle membrane sturdiness. "There's a basic panel of assays [tests] you can do to see if [a treatment] is making a difference, and it definitely is in the mice," said investigator Elisabeth Barton-Davis, who, like Sweeney and colleague Laurence Cordier, was funded by MDA.
Dr. Jerry R. Mendell, chairman of the Department of Neurology at Ohio State University Hospital in Columbus, reported, "Gene therapy is the future hope for the majority of Duchenne muscular dystrophy patients because most of those affected with this condition have large gene defects that are better treated by gene replacement. However, in other patients with small gene defects causing premature stop codons, the aminoglycoside antibiotics offer a different and potentially more immediate approach to treatment."
Mendell added, "I'm happy our painstaking efforts to prepare for muscular dystrophy gene therapy trials also have resulted in the identification of the candidates we need (those with confirmed premature stop codon defects) for a limited trial to determine the potential of carefully administered gentamicin injections for Duchenne muscular dystrophy."
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 (800) 572-1717, or visit MDA's Web site at www.mdausa.org. MDA programs are almost entirely funded by individual private contributors.
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