Authors:
Rebibo Sabbah, I. Nudelman, Z. M. Ahmed, T. B. Friedman, T. Baasov, and T. Ben-Yosef
Summary:
Type 1 Usher syndrome (USH1) is a recessively-inherited condition, characterized by profound prelingual deafness, vestibular areflexia, and prepubertal onset of retinitis pigmentosa (RP), which to date has no effective treatment. USH1 can be caused by mutations in each of at least six genes. While truncating mutations of these genes cause USH1, missense mutations of some of the same genes cause nonsyndromic deafness, suggesting that partial or low level activity of the encoded proteins may be sufficient for normal retinal function, although not for normal hearing. Interventions to enable at least some translation of full-length protein, may delay the onset and/or progression of RP in individuals with USH1 due to nonsense mutations. One such possible therapeutic approach is suppression of nonsense mutations by aminoglycosides. We demonstrated up to 91% suppression of PCDH15 nonsense mutations by commercial aminoglycosides in vitro. We also demonstrated ex vivo suppression, by the same aminoglycosides, of the R245X mutation. We are now testing suppression of several CDH23 nonsense mutations. In parallel, we are developing a series of new aminoglycoside-derived compounds, which includes two new promising derivatives, NB30 and NB54. Based on cell toxicity assays and on acute toxicity measurements in mice, the toxicity of both compounds is significantly reduced, in comparison to commercially available aminoglycosides. Based on in vitro and ex vivo experiments, their suppressive activity is maintained. The research described here will have important implications for development of targeted interventions that are effective for patients with USH1 and nonsyndromic RP caused by various nonsense mutations.
Source:
European Human Genetics Conference; 11:45AM, Tuesday, 06/03/08