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Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis

Leung, Amy; Sacristan-Reviriego, Almudena; Perdigão, Pedro RL; Sai, Hali; Georgiou, Michalis; Kalitzeos, Angelos; Carr, Amanda-Jayne F; ... van der Spuy, Jacqueline; + view all (2022) Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis. Stem Cell Reports 10.1016/j.stemcr.2022.08.005. (In press). Green open access

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Abstract

Leber congenital amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterized by severe sight impairment in infancy and rapidly progressing degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6) compared with control or CRISPR-corrected organoids. Increased levels of cGMP were detected. The translational readthrough-inducing drug (TRID) PTC124 was investigated as a potential therapeutic agent. LCA4 retinal organoids exhibited low levels of rescue of full-length AIPL1. However, this was insufficient to fully restore PDE6 in photoreceptors and reduce cGMP. LCA4 retinal organoids are a valuable platform for in vitro investigation of novel therapeutic agents.

Type: Article
Title: Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.stemcr.2022.08.005
Publisher version: https://doi.org/10.1016/j.stemcr.2022.08.005
Language: English
Additional information: © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: CRISPR-Cas9, LCA, Leber congenital amaurosis, ROs, TRID, gene editing, induced pluripotent stem cells, inherited retinal degeneration, renal epithelial cell reprogramming, retinal organoids, translation readthrough-inducing drug
UCL classification: 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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10155654
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