Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Abstract

Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

Retinal Pigment Epithelium Cell Death Is Associated With NLRP3 Inflammasome Activation by All-trans Retinal

“…4 An increasing body of evidence suggests that bisretinoid adducts derived from atRAL constitute the primary components of RPE lipofuscin, 1,24-28 and they have been identified as potential pathogenic factors in STGD1 and AMD. 28,29 A2E, a bisretinoid lipofuscin chromophore of RPE, reportedly activates NLRP3 inflammasome signaling in ARPE-19 cells. 30 In this study, we demonstrated that the A2E precursor atRAL activated NLRP3 inflammasome to trigger pyroptosis and apoptosis of ARPE-19 cells (Figs.…”

Low-Level Nighttime Light Therapy for Age-Related Macular Degeneration: A Randomized Clinical Trial

“…For example, fenretinide (4-hydoxy[phenyl]retinamide) is a retinoid derivative that competes with retinol for binding to retinol binding protein 4 (RBP4), thus reducing the delivery of all-trans-retinol to the RPE. 66,67 In contrast, the treatment emixustat (a derivative of all-trans-retinylamine) is a retinol mimic that inhibits the action of isomerohydrolase RPE65, Percentages given relate to total number in each cohort that completed the entire study duration (intervention, 20; control, 27). ''Growth/ shrinkage'' defines participants for whom an increase/decrease in drusen volume was reported over 12 months.…”

“…67,68 The hypothesis with both of these treatments, and other visual cycle modulating agents, is that, through slowing the visual cycle and the consequent reduction in formation of the toxic bisretinoid fluorophore A2E found in RPE lipofuscin, AMD progression will be slowed. 66,67,[69][70][71] Trial results for fenretinide did not show a statistically significant difference in geographic atrophy lesion size compared with placebo and the trend toward reduced lesion growth rates in those where RBP levels dropped below 2 mg/dL was also not statistically significant. 66 Similarly, a phase 2b/3 trial of emixustat in the treatment of geographic atrophy failed to reach its primary endpoint.…”

Seeing Eye to EyeVision: How it Works and What Can Go Wrongby John E.Dowling and Joseph L.DowlingMIT Press, Cambridge, MA, USA, 2016

“…The Dowlings report that that treatment with antioxidants for "dry" AMD and anti-VEGF therapy for "wet" AMD have had modest success. Some recent work suggests that treatments useful in lysosomal storage diseases or that complement antagonists are also worth a shot (6).…”