Nonsense suppression activity of PTC124 (ataluren)

Abstract

Auld et al. (1) suggest that PTC124's nonsense suppression activity may be an indirect consequence of the compound's effects on firefly luciferase (FLuc) enzymatic activity. However, our initial characterization of potential nonsense-suppressing compounds in FLuc assays also utilized independent assays of nonsense suppression in disease-relevant systems, including assays measuring synthesis of full-length protein in mdx myotubes, mdx mice, and Cftr−/− transgenic mice (2, 3). These tests eliminated inactive chemical scaffolds and identified PTC124. Subsequently, PTC124 demonstrated nonsense suppression activity in cystic fibrosis and Duchenne muscular dystrophy patients (2, 4). These independent confirmations in validated suppression assays are to be contrasted with Auld et al.'s (1) use of a Renilla luciferase reporter that was an unsuitable and misinterpreted gauge of nonsense suppression because it failed to respond appreciably to the established nonsense-suppressing aminoglycoside, G418.