1. PTC Therapeutics, 100 Corporate Court, South Plainfield, New Jersey 07080, USA
2. Department of Physiology, University of Pennsylvania School of Medicine, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA
3. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
4. These authors contributed equally to this work.

Correspondence to: Correspondence and requests for materials should be addressed to S.W.P. (Email: speltz@ptcbio.com).

Nonsense mutations promote premature translational termination and cause anywhere from 5–70% of the individual cases of most inherited diseases¹. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease^{2, 3}. To address the need for a drug capable of suppressing premature termination, we identified PTC124—a new chemical entity that selectively induces ribosomal readthrough 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. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

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