Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.
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.
Wagner
K R
KR
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. kwagner@mail.jhmi.edu
Hamed
S
S
Hadley
D W
DW
Gropman
A L
AL
Burstein
A H
AH
Escolar
D M
DM
Hoffman
E P
EP
Fischbeck
K H
KH
D000293:Adolescent; D001706:Biopsy; D015153:Blotting, Western; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics*; D003402:Creatine Kinase / Q000097:blood; D016189:Dystrophin / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005839:Gentamicins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016896:Treatment Outcome
D018389:Codon, Nonsense; D016189:Dystrophin; D005839:Gentamicins; D003402:Creatine Kinase