title: Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration.
abstract: Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human-induced pluripotent stem cells (hiPSCs) from patients with diagnosed AMD, including two donors with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from the AMD donors show significantly increased complement and inflammatory factors, which are most exaggerated in the ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discover that nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins and inflammatory and complement factors while upregulating nucleosome, ribosome, and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Department of Biomedical Sciences, University at Albany - SUNY, Albany, NY 12201, USA.
authors.forename: Janmeet S
authors.initials: JS
authors.lastname: Saini
authors.affiliation: Stem Cell Core Facility, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Corneo
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
authors.forename: Justine D
authors.initials: JD
authors.lastname: Miller
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kiehl
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Boles
authors.affiliation: Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Blenkinsop
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Stern
authors.affiliation: Neural Stem Cell Institute, Rensselaer, NY 12144, USA. Electronic address: sallytemple@neuralsci.org.
authors.forename: Sally
authors.initials: S
authors.lastname: Temple
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D008268:Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism*; D009536:Niacinamide / Q000627:therapeutic use*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide
keywords: age-related macular degeneration; aging; complement; drusen; human induced pluripotent stem cells; nicotinamide; retina; retinal pigment epithelium