In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome |
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Authors: | Annie Rebibo-Sabbah Igor Nudelman Zubair M Ahmed Timor Baasov Tamar Ben-Yosef |
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Institution: | (1) Department of Genetics, The Rappaport Family Institute for Research in the Medical Sciences, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa, 31096, Israel;(2) Department of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Haifa, 32000, Israel;(3) Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA |
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Abstract: | Type 1 Usher syndrome (USH1) is a recessively inherited condition, characterized by profound prelingual deafness, vestibular
areflexia, and prepubertal onset of retinitis pigmentosa (RP). While the auditory component of USH1 can be treated by cochlear
implants, to date there is no effective treatment for RP. USH1 can be caused by mutations in each of at least six genes. While
truncating mutations of these genes cause USH1, some missense mutations of the same genes cause nonsyndromic deafness. These
observations suggest that partial or low level activity of the encoded proteins may be sufficient for normal retinal function,
although not for normal hearing. In individuals with USH1 due to nonsense mutations, interventions enabling partial translation
of a full-length functional protein may delay the onset and/or progression of RP. One such possible therapeutic approach is
suppression of nonsense mutations by small molecules such as aminoglycosides. We decided to test this approach as a potential
therapy for RP in USH1 patients due to nonsense mutations. We initially focused on nonsense mutations of the PCDH15 gene, underlying USH1F. Here, we show suppression of several PCDH15 nonsense mutations, both in vitro and ex vivo. Suppression was achieved both by commercial aminoglycosides and by NB30, a
new aminoglycoside-derivative developed by us. NB30 has reduced cytotoxicity in comparison to commercial aminoglycosides,
and thus may be more efficiently used for therapeutic purposes. The research described here has important implications for
the development of targeted interventions that are effective for patients with USH1 caused by various nonsense mutations.
Annie Rebibo-Sabbah and Igor Nudelman contributed equally to this work. |
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