Radu Roxana A, Han Yun, Bui Tam V, Nusinowitz Steven, Bok Dean, Lichter Jay, Widder Ken, Travis Gabriel H, Mata Nathan L
Jules Stein Eye Institute, University of California, Los Angeles, California, USA.
Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4393-401. doi: 10.1167/iovs.05-0820.
Excessive accumulation of lipofuscin is observed in numerous degenerative retinal diseases. A toxic vitamin A-based fluorophore (A2E) present within lipofuscin has been implicated in the death of RPE and photoreceptor cells. Here, we used an animal model that manifests accelerated lipofuscin accumulation (ABCA4-/- mutant) to evaluate the efficacy of a therapeutic approach based on reduction of serum retinol.
N-(4-hydroxyphenyl)retinamide (HPR) potently and reversibly reduces serum retinol. The interaction of HPR with retinol binding protein (RBP) and transthyretin was studied by spectrofluorometry and size-exclusion chromatography. To assess the effects of HPR on visual cycle retinoids and A2E biosynthesis, HPR was chronically administered to ABCA4-/- mice. Mice were evaluated using biochemical, electrophysiological, and morphologic techniques.
Administration of HPR to ABCA4-/- mice caused immediate, dose-dependent reductions in serum retinol and RBP. Chronic administration produced commensurate reductions in visual cycle retinoids and arrested accumulation of A2E and lipofuscin autofluorescence in the RPE. Physiologically, HPR treatment caused modest delays in dark adaptation. Chromophore regeneration kinetics, light sensitivity of photoreceptors, and phototransduction processes were normal. Histologic examinations showed no alteration of retinal cytostructure or morphology.
These findings demonstrate the vitamin A-dependent nature of A2E biosynthesis and validate a novel therapeutic approach with potential to halt the accumulation of lipofuscin fluorophores in the eye.
在众多退行性视网膜疾病中均观察到脂褐素过度积累。脂褐素中存在的一种基于维生素A的有毒荧光团（A2E）与视网膜色素上皮（RPE）细胞和光感受器细胞的死亡有关。在此，我们使用一种表现出脂褐素积累加速的动物模型（ABCA4基因敲除突变体）来评估基于降低血清视黄醇的治疗方法的疗效。
N - （4 - 羟基苯基）视黄酰胺（HPR）能有效且可逆地降低血清视黄醇。通过荧光光谱法和尺寸排阻色谱法研究了HPR与视黄醇结合蛋白（RBP）和甲状腺素转运蛋白的相互作用。为了评估HPR对视觉循环类视黄醇和A2E生物合成的影响，对ABCA4基因敲除小鼠长期给予HPR。使用生化、电生理和形态学技术对小鼠进行评估。
给ABCA4基因敲除小鼠施用HPR导致血清视黄醇和RBP立即出现剂量依赖性降低。长期给药使视觉循环类视黄醇相应减少，并阻止了RPE中A2E和脂褐素自发荧光的积累。在生理上，HPR治疗导致暗适应出现适度延迟。生色团再生动力学、光感受器的光敏感性和光转导过程均正常。组织学检查显示视网膜细胞结构或形态无改变。
这些发现证明了A2E生物合成的维生素A依赖性，并验证了一种有潜力阻止眼部脂褐素荧光团积累的新治疗方法。
Zotero 插件