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Kerstin Nagel-Wolfrum, Tobias Goldmann, Fabian Möller, Nora Overlack, Valery Belakhov, Timor Baasov, Uwe Wolfrum; A Comparative Evaluation Of Translational Read-through Inducing Drugs For Treatment Of Ush. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5576. doi: https://doi.org/.
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Translational read-through inducing drugs (TRIDs), promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. We compare the efficacies of different TRIDs as a treatment option for nonsense mutation-based retinal disorders, focusing on the human Usher syndrome (USH). USH is the most frequent cause of inherited combined deaf-blindness. It is clinically and genetically heterogeneous, assigned to three clinical USH types and 11 known gene loci. So far no effective treatment for the ophthalmic component of USH exists. In USH, nonsense mutations account for ~11% of all disease-causing mutations.
We assessed retinal toxicities of TRIDs in mouse and human retinal explants by TUNEL-assays and immunofluorescence analyses applying molecular markers for retinal integrity. We generated constructs coding for disease-related nonsense mutations in USH1C and USH2A and quantified TRIDs induced read-through on the different USH causing nonsense mutations in HEK293T cells, mouse retinal explants and in vivo in mice.
In comparison with classical aminoglycoisdes (gentamicin), designer aminoglycosides and PTC124 exhibits significant better retinal biocompatibility. We observed a dose-dependent read-through of the USH nonsense mutations by TRIDs in transfected cultured cells. We demonstrate the functionality of the recovered proteins. In addition, we show TRIDs induced read-through in transfected retinal explants and in vivo in murine retinas.
The high biocompatibility combined with the good read-through efficacies of TRIDs emphasizes the potential of designer aminoglycosides and PTC124 in treating nonsense mutation-based retinal disorders, in particular for USH.
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