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PTC124 targets genetic disorders caused by nonsense mutations

Abstract

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 disease2,3. 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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Figure 1: PTC124 suppresses premature nonsense codons.
Figure 2: Full-length dystrophin is produced in PTC124-treated cultured myotubes.
Figure 3: Rescue of the dystrophic phenotype in muscles of the mdx mouse.
Figure 4: PTC124 activity is selective for readthrough of premature translation termination codons.

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Acknowledgements

This work was supported by an STTR grant to A.J. from the NIH and grants from the Muscular Dystrophy Association (USA) and Parent Project Muscular Dystrophy (USA) to H.L.S. We thank L. Cao and T. Komatsu for helpful discussions, G. Elfring for statistical support, D. Minn, X. Kang and S. Gothe for database mining and informatics expertise, and N. Garneau, S. I. Huq, and A. Bhattacharya for technical expertise. We thank K. Donnelly, C. Hirawat and F. P. Nigel for their effort, support and enthusiasm for the project. L. Gold, D. Goeddel and the late R. Swanson provided advice, encouragement and support at the onset of this project, which is gratefully acknowledged. We are grateful to the patients and their families and doctors for their participation in the clinical trial that generated the muscle biopsies and for their commitment during the development of PTC124.

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All authors have competing financial interests except E. Barton, P. Spatrick, F. He, M. Kawana and H. Feng.

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Welch, E., Barton, E., Zhuo, J. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91 (2007). https://doi.org/10.1038/nature05756

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