Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model.

Autor: Sharma R; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., George A; Pediatric, Developmental, & Genetic Ophthalmology Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Nimmagadda M; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Ortolan D; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Karla BS; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Qureshy Z; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Bose D; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Dejene R; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Liang G; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Wan Q; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Chang J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Jha BS; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Memon O; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Miyagishima KJ; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Rising A; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Lal M; Research Governance Council, FDA, White Oak, MD, USA., Hanson E; Intramural Research Program, NIAMS, National Institutes of Health, Bethesda, MD, 20892, USA., King R; Division of Preclinical Innovation, NCATS, National Institutes of Health, Rockville, MD, 20850, USA., Campos MM; Histology Core, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Ferrer M; Division of Preclinical Innovation, NCATS, National Institutes of Health, Rockville, MD, 20850, USA., Amaral J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., McGaughey D; Ophthalmic Genetics and Visual Functions Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Bharti K; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Kapil.Bharti@nih.gov.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Dec 15; Vol. 12 (1), pp. 7293. Date of Electronic Publication: 2021 Dec 15.
DOI: 10.1038/s41467-021-27488-x
Abstrakt: Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.
(© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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