Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

Publication date: Available online 26 January 2017
Source:Cell Stem Cell
Author(s): Janmeet S. Saini, Barbara Corneo, Justine D. Miller, Thomas R. Kiehl, Qingjie Wang, Nathan C. Boles, Timothy A. Blenkinsop, Jeffrey H. Stern, Sally Temple
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.

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Teaser

Saini et al. show that hiPSC-derived RPE, including ARMS2/HTRA1 homozygotes, from AMD patients exhibit higher complement and inflammatory factors compared to healthy controls. Nicotinamide treatment reduces these and other AMD-related molecules with no observed cytotoxicity. Pursuing nicotinamide's mechanism of action should reveal new therapeutic approaches for AMD.


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