Common antibiotic could treat some Duchenne muscular dystrophy patients - Other genetic diseases might yield to similar strategy

July 30, 1999

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.
-end-
The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the largest absolute growth in funding for research and training among all 125 medical schools in the country since 1991. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu).



University of Pennsylvania School of Medicine

Related Muscular Dystrophy Articles from Brightsurf:

Using CRISPR to find muscular dystrophy treatments
A study from Boston Children's Hospital used CRISPR-Cas9 to better understand facioscapulohumeral muscular dystrophy (FSHD) and explore potential treatments by systematically deleting every gene in the genome.

Duchenne muscular dystrophy diagnosis improved by simple accelerometers
Testing for Duchenne muscular dystrophy can require specialized equipment, invasive procedures and high expense, but measuring changes in muscle function and identifying compensatory walking gait could lead to earlier detection.

New therapy targets cause of adult-onset muscular dystrophy
The compound designed at Scripps Research, called Cugamycin, works by recognizing toxic RNA repeats and destroying the garbled gene transcript.

Gene therapy cassettes improved for muscular dystrophy
Experimental gene therapy cassettes for Duchenne muscular dystrophy have been modified to deliver better performance.

Discovery points to innovative new way to treat Duchenne muscular dystrophy
Researchers at The Ottawa Hospital and the University of Ottawa have discovered a new way to treat the loss of muscle function caused by Duchenne muscular dystrophy in animal models of the disease.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy
Massachusetts General Hospital researchers have found that extracellular RNA in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

Tamoxifen and raloxifene slow down the progression of muscular dystrophy
Steroids are currently the only available treatment to reduce the repetitive cycles of inflammation and disease progression associated with functional deterioration in patients with muscular dystrophy (MD).

Designed proteins to treat muscular dystrophy
The cell scaffolding holds muscle fibers together and protects them from damage.

Gene-editing alternative corrects Duchenne muscular dystrophy
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

GW researcher finds genetic cause of new type of muscular dystrophy
George Washington University & St. George's University of London research, published in The American Journal of Human Genetics, outlines a newly discovered genetic mutation associated with short stature, muscle weakness, intellectual disability, and cataracts, leading researchers to believe this is a new type of congenital muscular dystrophy.

Read More: Muscular Dystrophy News and Muscular Dystrophy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.