NIAMS-funded scientists at the University of Pennsylvania have successfully applied the common antibiotic gentamicin to restore the function of the protein dystrophin in mouse models of Duchenne muscular dystrophy (DMD). It is the absence of dystrophin that is responsible for this genetic muscle-wasting disease that affects 1 in 3,500 boys.
The discovery, say the scientists, may pave the way for a treatment in some human patients with DMD.
The work (J Clin Invest. 1999;104(4):1-7), co-funded by the Muscular Dystrophy Association and carried out under the direction of H. Lee Sweeney, Ph.D., took its cue from the known ability of a class of antibacterial antibiotics called aminoglycosides to suppress certain gene sequences, called "stop codons," that inhibit protein production. The scientists tested a specific aminoglycoside, gentamicin, on cultured muscle cells from the mdx mouse--an animal model for DMD that has a stop codon in the gene for dystrophin. The resulting restoration of dystrophin in cultured cells encouraged the researchers to try the antibiotic on the mice themselves. The result: dystrophin was restored to the cell membranes of all the striated mouse muscles they examined. Furthermore, the treatment afforded the muscles protection against injury.
"It appears that we may be witnessing the unfolding of a translational triumph in medical research--from culture dish to mouse and, hopefully, to human treatment," says the NIAMS' Director Stephen I. Katz, M.D., Ph.D. "There's certainly an air of excitement about what the Philadelphia group has accomplished."
The success of this mouse work has indeed fueled talk of testing in humans. The potential advantage of aminoglycosides for human DMD therapy may lie partly in the method of delivery. Gene therapy, the focus of much current interest for genetic disease treatment, works by using a "vector"--frequently a virus--to carry corrected genes to sites that will effect therapeutic change. Vectors, however, do not always hit their mark. By injecting an antibiotic, physicians could conceivably deliver the treatment more directly, simply, and systemically--a significant advantage in a disease affecting all the muscles in the body.
DMD is one of a group of genetic muscular dystrophies characterized by progressive weakness and degeneration of the skeletal or voluntary muscles that control movement. Nearly one-third of cases come from new mutations of the gene for dystrophin, which is unusually large and especially susceptible to mutations.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases.
Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. Journal of Clinical Investigation 1999;104(4):1-7.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), leads the Federal medical research effort in arthritis and musculoskeletal and skin diseases. The NIAMS supports research and research training throughout the United States, as well as on the NIH campus in Bethesda, MD, and disseminates health and research information. The National Institute of Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse is a public service sponsored by the NIAMS that provides health information and information sources. Additional information can be found on the NIAMS Web site at http://www.niams.nih.gov.