Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1.
Por:
Lukovic D, Artero Castro A, Kaya KD, Munezero D, Gieser L, Davó-Martínez C, Corton M, Cuenca N, Swaroop A, Ramamurthy V, Ayuso C and Erceg S
Publicada:
25 mar 2020
Resumen:
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.
Filiaciones:
:
Retinal Degeneration Lab, Research Center Principe Felipe, c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
National Stem Cell Bank-Valencia Node, Proteomics, Genotyping and Cell Line Platform, PRB3, Research Center Principe Felipe, c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain.
:
National Stem Cell Bank-Valencia Node, Proteomics, Genotyping and Cell Line Platform, PRB3, Research Center Principe Felipe, c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain
Kaya KD:
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA
Munezero D:
Departments of Ophthalmology, Biochemistry and Pharmaceutical and Pharmacological Sciences, West Virginia University, Morgantown, WV, 26506, USA
Gieser L:
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA
Davó-Martínez C:
National Stem Cell Bank-Valencia Node, Proteomics, Genotyping and Cell Line Platform, PRB3, Research Center Principe Felipe, c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain
Corton M:
Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid 28040, Spain
Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Cuenca N:
Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
Swaroop A:
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA
Ramamurthy V:
Departments of Ophthalmology, Biochemistry and Pharmaceutical and Pharmacological Sciences, West Virginia University, Morgantown, WV, 26506, USA
Ayuso C:
Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid 28040, Spain
Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
:
National Stem Cell Bank-Valencia Node, Proteomics, Genotyping and Cell Line Platform, PRB3, Research Center Principe Felipe, c/ Eduardo Primo Yúfera 3, 46012, Valencia, Spain
Stem Cells Therapies in Neurodegenerative Diseases Lab, Research Centre Principe Felipe, c/Eduardo Primo Yúfera 3, Valencia, Spain
Gold, Green Published
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