Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration.
Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration.
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DOI：
10.1016/j.stem.2016.12.015
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发表时间：
2017-05-04
期刊：
影响因子：
23.9
通讯作者：
Temple S
中科院分区：
文献类型：
--
作者：
Saini JS;Corneo B;Miller JD;Kiehl TR;Wang Q;Boles NC;Blenkinsop TA;Stern JH;Temple S
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 diagnosed with AMD, including two with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from AMD donors showed significantly increased complement and inflammatory factors, most exaggerated in ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discovered that Nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins, 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. Saini et al. show that hiPSC derived RPE from AMD patients, including ARMS2/HTRA1 homozygotes, 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.
