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

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.

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

“…These results thus strongly suggest that only a subset of DMD and CMD patients carrying stop mutations would potentially benefit of a gentamicin treatment aiming at suppressing premature termination codons. They may also explain the failure or relative difficulty to obtain significant improvement of symptoms in clinical trials already reported, [34][35][36] since the patients included in these trials were not chosen on the criteria of the response of their mutation. Similarly, Gentamicin and muscular dystrophies L Bidou et al our efforts to correct the albino phenotype associated with the platinum (Typ cÀp ) coat color mutation by local or systemic treatment with gentamicin at several stages during embryogenesis, in pups and in adults failed (data not shown).…”

Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product

“…12 The antibiotic gentamicin has been reported to increase read-through dystrophin protein over a premature stop codon, 13 and clinical trials have been conducted recently. 14 On the other hand, compensation for dystrophin lack by up-regulation of endogenous utrophin 15 is another possible strategy. These innovative strategies have not been successful because of several difficulties, including host immune response and low efficiency.…”

Thérapie spécifique d’allèle

“…Pour le gène de la dystrophine, les résultats des tests cliniques sont également nuancés. La protéine dystrophine entière a été détectée chez certains patients et atteignait jusqu'à 15 % du niveau de la protéine sauvage mais sans permettre un bénéfice thérapeutique clair [15][16][17]45]. Le succès de cette approche dépend du taux de réexpression de la protéine complète qui est nécessaire pour permettre un bénéfice thérapeutique.…”