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

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.
AuthorsAmy Leung, Almudena Sacristan-Reviriego, Pedro R L Perdigão, Hali Sai, Michalis Georgiou, Angelos Kalitzeos, Amanda-Jayne F Carr, Peter J Coffey, Michel Michaelides, James Bainbridge, Michael E Cheetham, Jacqueline van der Spuy
JournalStem cell reports (Stem Cell Reports) Vol. 17 Issue 10 Pg. 2187-2202 (10 11 2022) ISSN: 2213-6711 [Electronic] United States
PMID36084639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References
  • AIPL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Codon, Nonsense
  • Eye Proteins
  • Oxadiazoles
  • Guanosine Monophosphate
  • Phosphoric Diester Hydrolases
  • ataluren
Topics
  • Adaptor Proteins, Signal Transducing (genetics)
  • Carrier Proteins (genetics)
  • Child
  • Codon, Nonsense
  • Eye Proteins (genetics, metabolism)
  • Guanosine Monophosphate
  • Humans
  • Leber Congenital Amaurosis (genetics, therapy)
  • Organoids (metabolism)
  • Oxadiazoles
  • Phosphoric Diester Hydrolases (genetics)

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