title: A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation.
abstract: Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders.
authors.affiliation: Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goldmann
authors.forename: Nora
authors.initials: N
authors.lastname: Overlack
authors.forename: Fabian
authors.initials: F
authors.lastname: Möller
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Michiel
authors.initials: M
authors.lastname: van Wyk
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nagel-Wolfrum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: C540944:5-O-(5-amino-5-deoxyribofuranosyl)-1N-(4-amino-2-hydroxybutanoyl)paromamine; D048868:Adaptor Proteins, Signal Transducing; D000617:Aminoglycosides; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D010069:Oxadiazoles; C118970:USH1C protein, human; C515878:ataluren