Résumé :
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Nonsense mutations promote premature translational termination and cause anywhere from 5 to 70% of the individual cases of most inherited diseases. To address the need for a drug capable of suppressing premature termination, we developed PTC124, a new chemical entity and orally bioavailable compound that induces ribosomal read-through of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. Pharmacological and toxicological evaluation indicated that PTC124 is well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. In a Phase 2A clinical trial in DMD, approximately half of the patients sowed dystrophin expression in the EDB muscle after 28 days of drug exposure. Additionally there was a significant drop in plasmas CK levels in the patients. Cultured myotubes from the patients showed dose-dependent dystrophin expression in 100% of cases. Based on these findings, a blinded, placebo-controlled, long-term dosing trial in DMD has recently been initiated. In summary, based on its selectivity for premature stop codons, well-characterized activity profile, oral bioavailability, and pharmacological properties suggest that PTC124 may have broad clinical potential for the treatment of a large group of genetic disorders with limited therapeutic options.
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