Antibiotic-Mediated Readthrough to Treat Deafness Caused by Nonsense Mutations

Approximately 11% of all the genetic mutations that cause human disease are nonsense mutations, where a stop codon is inserted instead of a regular amino acid. Previous studies show that aminoglycoside antibiotics, as well as other compounds, can bind to specific sites on the ribosome and lead to “read-through” of the stop codon, resulting in expression of the full protein instead of a nonfunctional truncated protein. We recently demonstrated the efficiency of this approach by inducing “read-through” of nonsense mutations in the adenomatous polyposis coli nonsense gene in patients (Kariv et al. Int J Cancer, 2019). Over the years, our lab has identified many genetic mutations leading to deafness in both Israeli Jewish and Palestinian Arab cohorts. A large number of these mutations are nonsense mutations. To examine the possibility of inducing “read-through” in these genes, we are currently testing the following genes, GJB2, GPSM2, MYO3A, MYO7A, OTOG, PCDH15, POU3F4, PTPRQ and TMC1. for aminoglycoside induced “read-through”. However, aminoglycosides are ototoxic, rendering them ineffective for treating hearing loss. As an alternative, we are testing the macrolide antibiotics. Macrolide ototoxicity is dose-dependent, and thus careful dosage may be effective in inducing the nonsense mutation “read-through”, with no ototoxic effects. We have established a system in which the efficiency of the different drugs and the rescue potential of each variant can be tested in a multiplexed, systematic approach. Funded by the Tel Aviv University Breakthrough Innovative Research Grant.