Negamycin can restore dystrophin in mdx skeletal muscle

Rescuing nonsense mutations is of great scientific and clinical interest. In 1999, Barton-Davis et al. reported that gentamicin (GM), an aminoglycoside antibiotic that causes misreading of stop codons during translation, restored dystrophin function in the mdx mouse, an animal model of Duchenne-type muscular dystrophy (DMD), which results from a nonsense mutation in the dystrophin gene. Here we report that subcutaneous injection of a dipeptide antibiotic, negamycin (NM), also rescues mdx mice and restores dystrophin to skeletal muscle. Dystrophin expression in these mice was confirmed by immunohistochemistry and by Western blotting. NM also exhibited less toxicity than did GM. Mice survived after two weeks' administration of NM at doses 100 times higher than the minimum effective dose, whereas mice injected with similar levels of GM died within four hours after a single injection. These results suggest that NM might be a promising candidate for of DMD caused by nonsense mutations. NM may also provide a promising drug for correction of many other genetic diseases caused by nonsense mutations.