Nicotinamide: a novel treatment for age-related macular degeneration?

Abstract

Saini et al. recently reported in Cell StemCell that nicotinamide can suppress the expression of a broad set of genes in induced pluripotent stem cell-derived retinal pigment epithelium (iPS-RPE) cells that may contribute to age-related macular degeneration (AMD) (1). There are ample reasons to be excited about their findings, and many opportunities for future work. In this commentary, I will begin by providing background about the etiology of AMD before outlining some of the challenges of studying AMD using iPS-RPE. With that context in place, I will describe which elements of the Saini et al. study I find most exciting, and discuss potential future directions. The outer retina-a finely tuned machineThe outer half of the retina consists of hard working cells and structures that convert light into neural signals through phototransduction. Rod and cone photoreceptors initiate phototransduction when activated by light, but cannot complete the process without help from the multifunctional retinal pigment epithelium (RPE) or without fuel. Energy substrates for the RPE and photoreceptors are provided by a highly dense and fenestrated extraretinal vascular plexus, the choriocapillaris, which surrounds the outer retina ( Figure 1A).The choriocapillaris, RPE cells, and photoreceptors are all uniquely remarkable. According to many accounts, the blood flow rate and the vascular permeability of the choriocapillaris is higher than anywhere in the body (2).Oxygen and nutrients from the choriocapillaris are filtered and redistributed in the subretinal space through a pentalaminar matrix (Bruch's membrane) and by RPE cells. RPE also generate and secrete key vasculotrophic factors for choriocapillaris maintenance, deliver glucose to photoreceptors, recycle spent photopigments, absorb stray light, and phagocytose light damaged photoreceptor membranes to prevent oxidative stress (3). Photoreceptors can be activated by a single photon, and can respond appropriately to the wavelength and intensity of a light source. However, they are also extraordinarily metabolically demanding and inherently fragile (4). Maintaining the integrity and homeostasis of photoreceptors, RPE, and the choriocapillaris is imperative, and defects result in profound vision loss. Even finely tuned machines break down over timeThe prevalence of age-related vision loss should not be surprising considering the intense burdens placed on the choriocapillaris and RPE to support the remarkable metabolic demands of photoreceptors. In fact, AMD is a commonly occurring and leading cause of vision loss in industrialized countries. The global prevalence of AMD is steadily increasing and expected to reach epidemic proportions by the year 2040 when some experts estimate that 288 million people could be affected (5). To emphasize Editorial

Fructosamine-3-Kinase as a Potential Treatment Option for Age-Related Macular Degeneration

“…Because AMD is a multifactorial and complex disease with an unknown etiology, there is a need for drugs that exert rather broad effects on retinal physiology [ 33 ]. While it is already well known that a FN3K-catalyzed pathway removes ketoamines and prevents AGE production [ 34 ], our findings indicate for the first time some potential of the enzyme in the disruption of retinal AGEs.…”

“…However, it has to be mentioned that there is a scarcity of viable animal and cellular disease models [ 33 , 44 ]. Furthermore, developing reliable models is difficult since the initial events of AMD are caused by combinations of genetic and environmental factors that modify the photoreceptors, RPE, Bruch’s membrane and choriocapillaris, but not in a particular order [ 33 , 44 , 45 ]. In addition, while FN3K seems to be active against autofluorescent glycolaldehyde-derived AGEs, we currently do not know its potential effect on non-autofluorescent AGEs.…”

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

“…Oxidative stress-induced 661W cell death was markedly decreased by NMN treatment, with increases in antioxidant gene expression ( Nrf2 and Hmox-1 ). Although NMN therapy has gradually been reported to be beneficial for eye diseases [ 20 , 21 ], as far as we know, this report is the first to expand the role of NMN in a mouse model of retinal I/R injury induced by acute increases in intraocular pressure.…”

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

“…The process of mitophagy, in which damaged mitochondria are degraded and recycled, is pivotal for neuronal functions and the prevention of pathological neuronal dysfunction [ 202 ]. Impairments in this process have been associated with AMD and NAD + may be a potential solution for the impaired mitophagy [ 203 , 204 ]. PINK1 and PARKIN , which are responsible of the proper degradation of damaged mitochondria via mitophagy, appear to be upregulated in a mouse model of dry AMD, the erythroid 2-related factor 2/peroxisome proliferator-activated receptor gamma coactivator 1-alpha double knockdown, NFE2L2/PGC-1α −/− mouse model [ 205 ].…”