A comparative evaluation of NB30, NB54 and PTC124 in translational read‐through efficacy for treatment of an USH1C nonsense mutation

Abstract

Abstract Translational read‐through‐inducing drugs (TRIDs) promote read‐through of nonsense mutations, placing them in the spotlight of current gene‐based therapeutic research. Here, we compare for the first time the relative efficacies of new‐generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read‐through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf‐blindness. We quantify read‐through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read‐through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read‐through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full‐length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read‐through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation‐based retinal disorders.

Keywords

• drug therapy
• pharmacogenetics
• retinitis pigmentosa
• sensoneuronal degeneration
• Usher syndrome