Volume 1 Supplement 1

Proceedings of the First International Cilia in Development and Disease Scientific Conference (2012)

Open Access

Gene-based treatment options for Usher type 1C by translational read-through of a nonsense mutation

  • U Wolfrum1, 2Email author,
  • T Goldmann2,
  • N Overlack2,
  • F Möller2,
  • V Belakov3,
  • T Baasov3 and
  • K Nagel-Wolfrum2
Cilia20121(Suppl 1):O31

DOI: 10.1186/2046-2530-1-S1-O31

Published: 16 November 2012

The Usher syndrome (USH) is the most frequent cause of inherited combined deaf-blindness. The ciliopathy is clinically and genetically heterogeneous, assigned to three clinical USH types of which the most severe type is USH1. The USH1C gene encodes the PDZ containing scaffold protein harmonin which is expressed in form of numerous alternatively spliced variants. Hamonin binds directly to all USH1/2 proteins and is a key organizer of USH protein networks in photoreceptor cells. So far no effective treatment for the ophthalmic component of USH exists. Translational read-through was introduced as an innovative therapy option for several non-ocular diseases caused by nonsense mutations leading to a premature termination stop. Here we compare the potential of translational read-through inducing drugs (TRIDs), namely PTC124 (currently in clinical phase-II for non-ocular diseases) as well as the designer aminoglycoside NB30 and NB54 as a treatment option for patients carrying a nonsense mutation in the USH1C gene causing USH1. We examined read-through in cell culture, retinal cultures and in vivo in murine retinas. Restoration of the harmonin function was tested by GST pull-downs and actin filament bundling. The TRIDs recovered functional harmonin protein and showed an excellent biocompatibility in retinal cultures with read-through vs. toxicity evidently superior for NB54 and PTC124. In vivo administration of NB54 and PTC124 to mice induced recovery of full-length harmonin. The high biocompatibility combined with the sustained read-through efficacies of these novel drugs emphasizes the potential of TRIDs in treating nonsense mutations in USH as well as in other ciliopathies.

Authors’ Affiliations

Johannes Gutenberg University of Mainz
Cell & Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz
Edith and Joseph Fischer Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology


© Wolfram et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.