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Publication Detail
Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
  • Publication Type:
    Journal article
  • Authors:
    Leung A, Sacristan-Reviriego A, Perdigão PRL, Sai H, Georgiou M, Kalitzeos A, Carr A-JF, Coffey PJ, Michaelides M, Bainbridge J, Cheetham ME, van der Spuy J
  • Publisher:
    Elsevier BV
  • Publication date:
  • Journal:
    Stem Cell Reports
  • Medium:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • 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
  • Notes:
    © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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.
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