J. Biochem, 2003, Vol. 134, No. 5 751-758
© 2003 Japanese Biochemical Society
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Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx Mice
1 Department of Life Sciences, The University of Tokyo, 3-8-1 Komaba, Tokyo 153-8902; 2 Department of Tumor Biochemistry, Tokyo Metropolitan Institute of Medical Sciences, 3-18-22 Honkomagome, Tokyo 113-8613; 3 The Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Tokyo 141-0021; 4 Department of Otolaryngology, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655; 5 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639; and 6 Department of Molecular Therapy, National Institute of Neuroscience, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502
The ability of aminoglycoside antibiotics to promote read-through of nonsense mutations has attracted interest in these drugs as potential therapeutic agents in genetic diseases. However, the toxicity of aminoglycoside antibiotics may result in severe side effects during long-term treatment. In this paper, we report that negamycin, a dipeptide antibiotic, also restores dystrophin expression in skeletal and cardiac muscles of the mdx mouse, an animal model of Duchenne muscular dystrophy (DMD) with a nonsense mutation in the dystrophin gene, and in cultured mdx myotubes. Dystrophin expression was confirmed by immunohistochemistry and immunoblotting. We also compared the toxicity of negamycin and gentamicin, and found negamycin to be less toxic. Furthermore, we demonstrate that negamycin binds to a partial sequence of the eukaryotic rRNA-decoding A-site. We conclude that negamycin is a promising new therapeutic candidate for DMD and other genetic diseases caused by nonsense mutations.
* To whom correspondence should be addressed. Phone: +81-3-5454-6637, Fax: +81-3-5454-4306, E-mail: ryoichi{at}matsuda.c.u-tokyo.ac.jp