Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-62047-2
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Funding
- Institute of Health Carlos III (ISCIII)/ERDF (European Research Development Fund), Spain [PI16/00409]
- PE I + D + i 2013-2016 - ISCIII [PT17/0019/0024]
- ERDF
- ISCIII-ERDF [PI16/00425]
- CIBERER [06/07/0036]
- IIS-FJD Biobank [PT13/0010/0012]
- RAREGENOMICS - Regional Government of Madrid (CAM) [B2017/BMD3721]
- University Chair UAM-IIS-FJD of Genomic Medicine
- Spanish National Organization of the Blind (ONCE)
- Spanish Fighting Blindness Foundation (FUNDALUCE)
- Ramon Areces Foundation
- Miguel Servet I Program [CP18/00033]
- National Institute of Health [R01 EY028035, R01 EY025536]
- Intramural Research Program of the National Eye Institute [ZIAEY000450, ZIAEY000474]
- Miguel Servet I Program from ISCIII [CPII17_00006]
- NATIONAL EYE INSTITUTE [ZIAEY000546] Funding Source: NIH RePORTER
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Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a photoreceptor-specific chaperone that stabilizes the effector enzyme of phototransduction, cGMP phosphodiesterase 6 (PDE6). Mutations in the AIPL1 gene cause a severe inherited retinal dystrophy, Leber congenital amaurosis type 4 (LCA4), that manifests as the loss of vision during the first year of life. In this study, we generated three-dimensional (3D) retinal organoids (ROs) from human induced pluripotent stem cells (hiPSCs) derived from an LCA4 patient carrying a Cys89Arg mutation in AIPL1. This study aimed to (i) explore whether the patient hiPSC-derived ROs recapitulate LCA4 disease phenotype, and (ii) generate a clinically relevant resource to investigate the molecular mechanism of disease and safely test novel therapies for LCA4 in vitro. We demonstrate reduced levels of the mutant AIPL1 and PDE6 proteins in patient organoids, corroborating the findings in animal models; however, patient-derived organoids maintained retinal cell cytoarchitecture despite significantly reduced levels of AIPL1.
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