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A. Rebibo Sabbah, I. Nudelman, T. Baasov, T. Ben-Yosef; Evaluating Suppression of Nonsense Mutations by Aminoglycoside Antibiotics as an Intervention for Vision Loss in Type I Usher Syndrome. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2809.
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© ARVO (1962-2015); The Authors (2016-present)
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 is genetically heterogeneous. While truncating mutations of certain 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. One possible therapeutic approach allowing at least some translation of full-length protein is suppression of nonsense mutations by small molecules such as aminoglycoside antibiotics.
Suppression of nonsense mutations was initially tested in vitro, using a transcription/ translation assay of a reporter plasmid harboring various nonsense mutations of CDH23 and PCDH15, underlying USH1D and USH1F, respectively. Ex vivo suppression is tested using expression constructs transfected into cultured cells. In parallel, we are developing a series of new aminoglycoside-derived compounds, which will maintain their suppressive activity, while having reduced toxicity.
We demonstrated, in vitro, suppression of various PCDH15 and CDH23 nonsense mutations, by commercial aminoglycosides. We also demonstrated ex vivo suppression, by the same aminoglycosides, of one mutation. We are currently generating constructs for ex vivo testing of CDH23 murine nonsense mutations, towards assays in existing mouse models for USH1D. In vitro and ex vivo experiments of two newly synthesized derivatives proved both a suppressive activity and a significantly reduced toxicity of these compounds in comparison to commercially available aminoglycosides.
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.
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