Readthrough strategies for stop codons in Duchenne muscular dystrophy.
Duchenne muscular dystrophy is due to mutations of the dystrophin gene. These are large deletions or duplications in 80% of cases, while premature stop codons (nonsense point mutations) account for 7% of cases. This subgroup of patients may take advantage of the properties of the antibiotic gentamicin to suppress stop codons (readthrough). The efficiency of the readthrough varies inversely to the efficiency of a stop codon and is also affected by the different components of the drug. Following gentamicin treatment of mdx mice, dystrophin was re-expressed up to 20% of normal level, albeit with variability among animals. Human trials with gentamicin have so far obtained doubtful results. PTC124 belongs to a new class of small molecules that mimics at lower concentrations the readthrough activity of gentamicin. The administration of PTC124 resulted in the production of full-length and functionally active dystrophin both in vitro and in mdx mice. A Phase II clinical trial is now in course and will be terminated at the end of 2006.
Aurino
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S
Telethon Institute of Genetics and Medicine, Naples, Italy.
Nigro
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D000617:Aminoglycosides / Q000627:therapeutic use*; D000818:Animals; D018388:Codon, Terminator / Q000235:genetics*; D016189:Dystrophin / Q000235:genetics*; D006801:Humans; D051379:Mice; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics*; D020135:Peptide Nucleic Acids / Q000627:therapeutic use*
D000617:Aminoglycosides; D018388:Codon, Terminator; D016189:Dystrophin; D020135:Peptide Nucleic Acids