A common antibiotic called gentamicin might be able to completely arrest disease progression in a significant number of Duchenne muscular dystrophy patients, according to a new study from the University of Pennsylvania Medical Center.
In about 15 percent of Duchenne patients, the disease is caused by a specific type of genetic mutation called a premature stop codon in the dystrophin gene, and it is this group that might benefit from the treatment strategy, so far demonstrated only in mice. Additionally, the approach might prove effective for a similar subset of people suffering from other genetic disorders. A report on the study appears in the August 15 issue of the Journal of Clinical Investigation, and small-scale clinical trials based on the findings are being planned.
"For those Duchenne muscular dystrophy patients with this particular type of genetic mutation, gentamicin might well be an effective treatment," says H. Lee Sweeney, PhD, chairman of the department of physiology and senior author on the new report. "A similar therapeutic strategy might also be useful in treating a number of other diseases involving the same kind of genetic error."
Duchenne muscular dystrophy is caused by unwanted alterations in the gene that codes for a large protein called dystrophin, required for muscle cells to survive the rigors of use. Mutations can occur anywhere in the gene, however, and not all mutations are equal. In about 15 percent of Duchenne patients, a genetic error called a premature stop codon signals cellular protein-production machinery to cease work in midstream, before the job is done. The result is a useless fragment of the dystrophin protein that is promptly removed by the cell.
Working with mdx mice - a strain of mice deficient in dystrophin because of such a mutation - the Penn team showed that closely controlled doses of the antibiotic gentamicin allowed the cellular machinery to read through the stop signal and complete production of the full dystrophin protein. Treated mdx mice produced sufficient levels of dystrophin to stop progression of their muscular dystrophy.
Gentamicin is a powerful antibiotic with the potential of major side effects, including permanent deafness and kidney damage, Sweeney notes. A treatment protocol, however, could be tailored to protect against side effects. The drug might be given only once a day, for example, to induce a period of production of the dystrophin protein, allowing the remainder of the day for drug clearance from the body. Because the dystrophin protein persists well in the body, gentamicin administration might also be discontinued periodically. Additionally, drugs are available that can minimize the side effects of gentamicin.
"The real hope here is that this approach will stabilize this group of Duchenne muscular dystrophy patients long enough for other treatments such as gene therapy to become available," Sweeney says. "In the meantime, if we can manage the potential side effects of gentamicin, we may be able to improve the lives of a significant number of people."
Small, short-term clinical trials involving about 15 patients with identified premature stop codon mutations in the dystrophin gene are planned for the near future. The aim would be to demonstrate that the administration of gentamicin leads to the production of functional dystrophin protein in the body. If this can be shown, a larger, longer-term trial will be proposed. Because gentamicin has already been approved by the federal Food and Drug Administration, the researchers hope to make relatively rapid progress in exploring this new use of the drug.
The lead author on the study is Elisabeth R. Barton-Davis, PhD. The coauthors are Laurence Cordier, PhD, Daria I. Shoturma, and Stuart E. Leland, DVM. The work was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association. The Muscular Dystrophy Association also funded fellowships for Barton-Davis and Cordier.
Materials provided by University Of Pennsylvania Medical Center. Note: Content may be edited for style and length.
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