Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations

Authors

  • Kathryn R. Wagner MD, PhD,

    Corresponding author
    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
    2. Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD
    • Department of Neurology, The Johns Hopkins Hospital, 607 PCTB, 725 North Wolfe Street, Baltimore, MD 21205
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  • Sherifa Hamed MD,

    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
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  • Donald W. Hadley MS,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
    2. Medical Genetics Branch/National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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  • Andrea L. Gropman MD,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
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  • Aaron H. Burstein PharmD,

    1. Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, MD
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  • Diana M. Escolar MD,

    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
    2. Department of Neurology, George Washington University, Washington, DC
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  • Eric P. Hoffman PhD,

    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
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  • Kenneth H. Fischbeck MD

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
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  • This article is a US Government work and, as such, is in the public domain of the United States of America.

Abstract

Aminoglycosides have previously been shown to suppress nonsense mutations, allowing translation of full-length proteins in vitro and in animal models. In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype. A subset of patients with Duchenne and Becker muscular dystrophy similarly possess a nonsense mutation, causing premature termination of dystrophin translation. Four such patients, with various stop codon sequences, were treated once daily with intravenous gentamicin at 7.5 mg/kg/day for 2 weeks. No ototoxicity or nephrotoxicity was detected. Full-length dystrophin was not detected in pre- and post-treatment muscle biopsies.

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