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

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.

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

“…Translational read-through drugs can insert a random amino acid at the nonsense mutation site by changing mRNA conformation, thereby preventing translation premature stop. Among these drugs, molecules NB54 and PTC124 have been tested to suppress a nonsense mutation, p.R31X, of the USH1C gene in vivo [187]. Subretinal injection of NB54 and PTC124 is able to restore protein expression of full-length harmonin in mice.…”

Therapeutics Based on Stop Codon Readthrough

“…For example, the NB54 aminoglycoside derivative suppressed nonsense mutations associated with CF, DMD, MPS I-H, Rett syndrome, and Usher syndrome in cultured cells more efficiently than gentamicin (13, 47, 94, 111, 139). In addition, NB54 suppressed PTCs in mouse models of CF and MPS I-H more efficiently than gentamicin (111, 139).…”

A review of patents (2011–2015) towards combating resistance to and toxicity of aminoglycosides

“…Furthermore, NB30 and NB54 were evaluated for readthrough efficiency for treatment of USH1C nonsense mutation, and in vivo administration of NB54 induced the recovery of full-length harmonin 1a with ehhanced efficiency. 208 NB54 was tested for its ototoxicity and enhanced suppression of CF PTCs. NB54 was shown to partially restore halide efflux in a CF bronchial epithelial cell line, but not in a CF cell line lacking a PTC.…”