Aminoglycoside antibiotics restore dystrophin function to skeletal musclesof mdx mice

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein in striated muscle. A significant number of these mutations are premature stop codons. On the b asis of the observation that aminoglycoside treatment carl suppress stop co dons in cultured cells, we tested the effect of gentamicin on cultured musc le cells from the mdx mouse - an animal model for DMD that possesses a prem ature stop codon in the dystrophin gene. Exposure of mdx myotubes to gentam icin led to the expression and localization of dystrophin to the cell membr ane. We then evaluated the effects of differing dosages of gentamicin on ex pression and functional protection of the muscles of mdx mice. We identifie d a treatment regimen that resulted in the presence of dystrophin in the ce ll membrane in all striated muscles examined and that provided functional p rotection against muscular injury. To our knowledge, our results are the fi rst to demonstrate that aminoglycosides can suppress stop codons not only i n vitro but also in vivo. Furthermore, these results raise the possibility of a novel treatment regimen fbr muscular dystrophy and other diseases caus ed by premature stop codon mutations. This treatment could prove effective in up to 15% of patients with DMD.