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

Abstract

Summary 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.

Nicotinamide as a treatment option of Age-Related Macular Degeneration

“…Combined with a prolonged lifetime expectation in developed countries, AMD is developing to a social and economic burden. Therefore, there is an urgent need for a treatment of AMD that can delay disease manifestation and progression for several years.In a recent manuscript, Saini and colleagues analyzed a vitamin B derivate, nicotinamide (NAM), as a potential treatment strategy of AMD [4]. The antiin lammatory activity of NAM is not entirely new and may have inspired the investigators to look in detail at the effect of this drug for AMD treatment.…”

“…Collectively NAM was identi ied as a cytoprotectant that blocks cellular in lammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation [6]. Therefore, NAM supplementation was suggested for the treatment of chronic diseases with an immune system dysfunction as seen in diabetes and agerelated diseases.Sinai et al [4], investigated the effects of NAM in a human induced pluripotent stem cell (iPSC) model of AMD which they they previously established. The advantage of this model is evident.…”

“…In a recent manuscript, Saini and colleagues analyzed a vitamin B derivate, nicotinamide (NAM), as a potential treatment strategy of AMD [4]. The antiin lammatory activity of NAM is not entirely new and may have inspired the investigators to look in detail at the effect of this drug for AMD treatment.…”

“…Sinai et al [4], investigated the effects of NAM in a human induced pluripotent stem cell (iPSC) model of AMD which they they previously established. The advantage of this model is evident.…”

“…Given the strong involvement of complement in AMD (genetic association [7], complement proteins in drusen [4,8,9], ARMS2 protein function in complement [10], fctor H on microglial [11] and the dramatic reduction of C3 expression levels in iPSC-RPE lines upon NAM treatment, justi ied the question by the investigators whether the NAM effect was largely explained by the reduction of C3 transcription. To answer this question, the authors inhibited C3 expression in their iPSC cell models via shRNA.…”