RESUMEN
Impaired dark adaptation (DA), a defect in the ability to adjust to dimly lit settings, is a universal hallmark of aging. However, the mechanisms responsible for impaired DA are poorly understood. Vitamin A byproducts, such as vitamin A dimers, are small molecules that form in the retina during the vitamin A cycle. We show that later in life, in the human eye, these byproducts reach levels commensurate with those of vitamin A. In mice, selectively inhibiting the formation of these byproducts, with the investigational drug C20D3-vitamin A, results in faster DA. In contrast, acutely increasing these ocular byproducts through exogenous delivery leads to slower DA, with otherwise preserved retinal function and morphology. Our findings reveal that vitamin A cycle byproducts alone are sufficient to cause delays in DA and suggest that they may contribute to universal age-related DA impairment. Our data further indicate that the age-related decline in DA may be tractable to pharmacological intervention by C20D3-vitamin A.
Asunto(s)
Adaptación a la Oscuridad/fisiología , Retina/metabolismo , Vitamina A/metabolismo , Envejecimiento , Animales , Adaptación a la Oscuridad/genética , Ojo/efectos de los fármacos , Ojo/metabolismo , Humanos , Degeneración Macular/fisiopatología , Masculino , Ratones , Ratones Endogámicos ICR , Retina/efectos de los fármacos , Degeneración Retiniana/fisiopatología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Agudeza Visual/efectos de los fármacos , Agudeza Visual/fisiología , Vitamina A/antagonistas & inhibidores , Vitamina A/fisiologíaRESUMEN
PURPOSE: This article investigates the relationship between visual acuity (VA), total area of geographic atrophy (GA), and percentage of foveal GA. METHODS: A multicenter, retrospective, cross-sectional study was conducted of patients with GA due to age-related macular degeneration. Demographics, VA, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT) images were collected. Using FAF images aided by SD-OCT, fovea-sparing status, GA pattern, total GA size, and percentage of GA covering the foveal area-within a 1.5-mm-diameter circle centered on the fovea centralis-were assessed. Univariable and multiple linear regression analyses were performed. RESULTS: Fifty-four eyes (mean age, 78.7 ±7.7 years [SD], 60.0% female) were studied. Mean VA was 0.8 ± 0.6 logarithm of the minimum angle of resolution (Snellen equivalent 20/126 ± 20/80), mean total GA 8.8 ± 6.7 mm2, and mean percentage of foveal GA was 71.5 ± 30.9%. Of all assessed eyes, 48.2% (n = 26) presented with multifocal GA, and 18.5% (n =10) had foveal sparing. Multiple regression analysis revealed that, controlling for age and GA pattern, the percentage of foveal GA presented a statistically significant association with VA (ß =0.41, P = .004). No significant associations were observed with mean total GA size, while controlling for the same variables (ß=0.010, P = .440). CONCLUSIONS: Percentage of foveal GA was significantly associated with VA impairment, although the same was not verified for total GA area. These findings suggest that percentage of foveal GA may represent a more useful tool for assessing the impact of GA on VA. Further validation is needed in larger cohorts.
RESUMEN
One of the earliest events preceding several forms of retinal degeneration is the formation and accumulation of vitamin A dimers in the retinal pigment epithelium (RPE) and underlying Bruch's membrane (BM). Such degenerations include Stargardt disease, Best disease, forms of retinitis pigmentosa, and age-related macular degeneration (AMD). Since their discovery in the 1990's, dimers of vitamin A, have been postulated as chemical triggers driving retinal senescence and degeneration. There is evidence to suggest that the rate at which vitamin A dimerizes and the eye's response to the dimerization products may dictate the retina's lifespan. Here, we present outstanding questions, finding the answers to which may help to elucidate the role of vitamin A dimerization in retinal degeneration.
Asunto(s)
Fluorescencia , Fondo de Ojo , Lipofuscina/química , Retina/patología , Degeneración Retiniana/patología , Vitamina A/química , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Lámina Basal de la Coroides/química , Lámina Basal de la Coroides/metabolismo , Lámina Basal de la Coroides/patología , Dimerización , Humanos , Lipofuscina/metabolismo , Modelos Químicos , Estructura Molecular , Retina/metabolismo , Degeneración Retiniana/metabolismo , Epitelio Pigmentado de la Retina/química , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Vitamina A/metabolismoRESUMEN
We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway.