PTC124-Mediated Translational Readthrough of a Nonsense Mutation Causing Usher Syndrome Type 1C

• DOI: 10.1089/hum.2010.067
• Publication Date: 2011-01-14T16:31:18Z
• Authors: T. Goldmann; N. Overlack; U. Wolfrum; K. Nagel-Wolfrum
• Keywords: 0301 basic medicine; Oxadiazoles; Genetic Vectors; Cell Cycle Proteins; Retina; 3. Good health; Mice, Inbred C57BL; Cytoskeletal Proteins; Luminescent Proteins; Mice; 03 medical and health sciences; Electroporation; Microscopy, Fluorescence; Codon, Nonsense; Animals; Humans; Gentamicins; Usher Syndromes; Cells, Cultured; Adaptor Proteins, Signal Transducing; Red Fluorescent Protein

We investigated the therapeutic potential of the premature termination codon (PTC) readthrough-inducing drug PTC124 in treating the retinal phenotype of Usher syndrome, caused by a nonsense mutation in the USH1C gene. Applications in cell culture, organotypic retina cultures, and mice in vivo revealed significant readthrough and the recovery of protein function. In comparison with other readthrough drugs, namely the clinically approved readthrough-inducing aminoglycoside gentamicin, PTC124 exhibits significant better retinal biocompatibility. Its high readthrough efficiency in combination with excellent biocompatibility makes PTC124 a promising therapeutic agent for PTCs in USH1C, as well as other ocular and nonocular genetic diseases.