Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis.
Stem Cell Reports
; 17(10): 2187-2202, 2022 10 11.
Article
en En
| MEDLINE
| ID: mdl-36084639
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Amaurosis Congénita de Leber
Tipo de estudio:
Risk_factors_studies
Límite:
Child
/
Humans
Idioma:
En
Revista:
Stem Cell Reports
Año:
2022
Tipo del documento:
Article
País de afiliación:
Reino Unido