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Posters-Accepted Abstracts: J Clin Exp Ophthalmol
Hereditary retinal dystrophies are a genetically heterogeneous group of rare disorders that causes vision defects, for which currently no effective cure is available. Patient screenings predict that ~12% of all pathogenic variants identified in patients are nonsense mutations. Therefore, a therapy that targets nonsense mutations has great potential to be beneficial for a substantial cohort making the approach both practical and economical. Nonsense mutations introduce a premature termination codon in the coding sequence of genes and lead to the expression of truncated, non-functional protein. Translational read-through mediates the over-read of nonsense mutations and thereby induces the expression of functional full-length proteins. We studied the biocompatibility of different translational read-through inducing drugs (TRIDs) as well as the read-through efficacies for different nonsense mutations causing retinal dystrophies with the spotlight on the Usher syndrome (USH) which is the most common form of combined deaf-blindness in man. Our data show that in comparison with classical aminoglycosides (e.g. gentamicin), designer aminoglycosides, like NB84 as well as the chemical compound Ataluren exhibit very good retinal biocompatibility. Our studies conclusively revealed read-through of different USH causing mutations and related ciliopathies, namely subtypes of the Bardet-Biedl syndrome and the Senior Loken syndrome by TRIDs in cultured cells. Furthermore, we demonstrated read-through in organotypic retina cultures, and in vivo in mice. In summary, our data indicate that the excellent biocompatibility combined with the ample read-through efficacies of TRIDs emphasizes the potential of designer aminoglycosides and Atalurenas a treatment option for retinal disorders caused byin-frame nonsense mutation.