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

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 fr...

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Autores principales: Leung, Amy, Sacristan-Reviriego, Almudena, Perdigão, Pedro R.L., Sai, Hali, Georgiou, Michalis, Kalitzeos, Angelos, Carr, Amanda-Jayne F., Coffey, Peter J., Michaelides, Michel, Bainbridge, James, Cheetham, Michael E., van der Spuy, Jacqueline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561542/
https://www.ncbi.nlm.nih.gov/pubmed/36084639
http://dx.doi.org/10.1016/j.stemcr.2022.08.005
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author Leung, Amy
Sacristan-Reviriego, Almudena
Perdigão, Pedro R.L.
Sai, Hali
Georgiou, Michalis
Kalitzeos, Angelos
Carr, Amanda-Jayne F.
Coffey, Peter J.
Michaelides, Michel
Bainbridge, James
Cheetham, Michael E.
van der Spuy, Jacqueline
author_facet Leung, Amy
Sacristan-Reviriego, Almudena
Perdigão, Pedro R.L.
Sai, Hali
Georgiou, Michalis
Kalitzeos, Angelos
Carr, Amanda-Jayne F.
Coffey, Peter J.
Michaelides, Michel
Bainbridge, James
Cheetham, Michael E.
van der Spuy, Jacqueline
author_sort Leung, Amy
collection PubMed
description 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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spelling pubmed-95615422022-10-15 Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis Leung, Amy Sacristan-Reviriego, Almudena Perdigão, Pedro R.L. Sai, Hali Georgiou, Michalis Kalitzeos, Angelos Carr, Amanda-Jayne F. Coffey, Peter J. Michaelides, Michel Bainbridge, James Cheetham, Michael E. van der Spuy, Jacqueline Stem Cell Reports Article 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. Elsevier 2022-09-08 /pmc/articles/PMC9561542/ /pubmed/36084639 http://dx.doi.org/10.1016/j.stemcr.2022.08.005 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Leung, Amy
Sacristan-Reviriego, Almudena
Perdigão, Pedro R.L.
Sai, Hali
Georgiou, Michalis
Kalitzeos, Angelos
Carr, Amanda-Jayne F.
Coffey, Peter J.
Michaelides, Michel
Bainbridge, James
Cheetham, Michael E.
van der Spuy, Jacqueline
Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title_full Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title_fullStr Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title_full_unstemmed Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title_short Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis
title_sort investigation of ptc124-mediated translational readthrough in a retinal organoid model of aipl1-associated leber congenital amaurosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561542/
https://www.ncbi.nlm.nih.gov/pubmed/36084639
http://dx.doi.org/10.1016/j.stemcr.2022.08.005
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