Torriano, S;
Erkilic, N;
Baux, D;
Cereso, N;
De Luca, V;
Meunier, I;
Moosajee, M;
... Kalatzis, V; + view all
(2018)
The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy.
Scientific Reports
, 8
, Article 8234. 10.1038/s41598-018-26481-7.
Preview |
Text
Torriano_effectPTC124.pdf - Published Version Download (2MB) | Preview |
Abstract
Inherited retinal dystrophies (IRDs) are caused by mutations in over 200 genes, resulting in a range of therapeutic options. Translational read-through inducing drugs (TRIDs) offer the possibility of treating multiple IRDs regardless of the causative gene. TRIDs promote ribosomal misreading of premature stop codons, which results in the incorporation of a near-cognate amino acid to produce a full-length protein. The IRD choroideremia (CHM) is a pertinent candidate for TRID therapy, as nonsense variants cause 30% of cases. Recently, treatment of the UAA nonsense-carrying CHM zebrafish model with the TRID PTC124 corrected the underlying biochemical defect and improved retinal phenotype. To be clinically relevant, we studied PTC124 efficiency in UAA nonsense-carrying human fibroblasts and induced pluripotent stem cell-derived retinal pigment epithelium, as well as in a UAA-mutated CHM overexpression system. We showed that PTC124 treatment induces a non-significant trend for functional rescue, which could not be improved by nonsense-mediated decay inhibition. Furthermore, it does not produce a detectable CHM-encoded protein even when coupled with a proteasome inhibitor. We suggest that drug efficiency may depend upon on the target amino acid and its evolutionary conservation, and argue that patient cells should be screened in vitro prior to inclusion in a clinical trial.
| Type: | Article |
|---|---|
| Title: | The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41598-018-26481-7 |
| Publisher version: | http://dx.doi.org/10.1038/s41598-018-26481-7 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, DUCHENNE MUSCULAR-DYSTROPHY, TRANSLATIONAL READ-THROUGH, RAB GERANYLGERANYL TRANSFERASE, PREMATURE TERMINATION CODONS, LEBERS CONGENITAL AMAUROSIS, MESSENGER-RNA DECAY, LONG-QT SYNDROME, NONSENSE MUTATIONS, GENE-THERAPY, MOUSE MODEL |
| 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-pp.ucl.ac.uk/id/eprint/10058239 |
Archive Staff Only
 |
View Item |
