Richardson, R;
Smart, M;
Tracey-White, D;
Webster, AR;
Moosajee, M;
(2017)
Mechanism and evidence of nonsense suppression therapy for genetic eye disorders.
Experimental Eye Research
, 155
pp. 24-37.
10.1016/j.exer.2017.01.001.
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Abstract
Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner. This approach aims to suppress the fidelity of the ribosome during protein synthesis so that a near-cognate aminoacyl-tRNA, which shares two of the three nucleotides of the PTC, can be inserted into the peptide chain, allowing translation to continue, and a full-length functional protein to be produced. Here we discuss the mechanisms and evidence of nonsense suppression agents, including the small molecule drug ataluren (or PTC124) and next generation 'designer' aminoglycosides, for the treatment of genetic eye disease.
| Type: | Article |
|---|---|
| Title: | Mechanism and evidence of nonsense suppression therapy for genetic eye disorders |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.exer.2017.01.001 |
| Publisher version: | http://dx.doi.org/10.1016/j.exer.2017.01.001 |
| Language: | English |
| Additional information: | © 2017 Elsevier Ltd. All rights reserved. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher. |
| Keywords: | Aminoglycosides, Ataluren, Genetic eye disease, Nonsense mutation, Nonsense suppression therapy, Premature termination codon, Readthrough, Translational bypass |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1536564 |
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