Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

Int J Mol Sci. 2019 Dec 12;20(24):6274. doi: 10.3390/ijms20246274.


The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2AG3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs.

Keywords: Ataluren; Retinitis pigmentosa; TRID; Usher syndrome; ocular therapy; patient-derived fibroblasts; translational read-through.

MeSH terms

  • Cells, Cultured
  • Codon, Nonsense*
  • Extracellular Matrix Proteins / chemistry
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Models, Biological
  • Mutation
  • Oxadiazoles / pharmacology
  • Oxadiazoles / therapeutic use*
  • Protein Biosynthesis / drug effects
  • Structure-Activity Relationship
  • Usher Syndromes / diagnosis
  • Usher Syndromes / drug therapy*
  • Usher Syndromes / genetics*


  • Codon, Nonsense
  • Extracellular Matrix Proteins
  • Oxadiazoles
  • USH2A protein, human
  • ataluren

Supplementary concepts

  • Usher syndrome, type 2A