Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Autor:	Dalvi S; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Roll M; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Chatterjee A; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Kumar LK; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Bhogavalli A; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Foley N; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Arduino C; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Spencer W; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Reuben-Thomas C; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA., Ortolan D; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institute of Health, Bethesda, MD, USA., Pébay A; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia., Bharti K; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institute of Health, Bethesda, MD, USA., Anand-Apte B; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Singh R; Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA. Electronic address: ruchira_singh@urmc.rochester.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2024 Dec 16; Vol. 59 (24), pp. 3290-3305.e9. Date of Electronic Publication: 2024 Oct 02.
DOI:	10.1016/j.devcel.2024.09.006
Abstrakt:	Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs. Competing Interests: Declaration of interests University of Rochester has filed a provisional US patent application: U.S. Provisional Patent Application No. 63/632,123, filed April 10, 2024, title: “Drug Treatment for Macular Degeneration.” (Published by Elsevier Inc.)
Databáze:	MEDLINE
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