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

Abstract

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.

• Authors: Ananya Samanta, Katarina Stingl, Susanne Kohl, Jessica Ries, Joshua Linnert, Kerstin Nagel-Wolfrum
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 24 (Dec 12 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31842393 (Publication Type: Journal Article)

Chemical References

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

Topics

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