Evaluating therapeutic potential of a novel PPAR-a agonist for wet-AMD

项目总结 这项建议的目的是评估一种新的PPAR-α激动剂A91的治疗潜力，用于 治疗湿性老年性黄斑变性(湿AMD)。目前的护理标准 湿性AMD或其他具有明显微血管基础的眼部疾病， 主要依靠管理异常血管的生长。在这样做的时候，治疗 选项使用固有的侵入性程序，受到技术限制和财务方面的挑战 约束条件。例如，成本高，需要专门的设备，重复玻璃体内 注射和有限的病人反应是医疗保健进展的一些关键障碍 适用于湿性AMD。因此，开发用于全身给药的小分子将 显著改善当前护理标准的各个方面。作为实验证据 提示，PPAR-α在多种疾病模型中的药理激活具有治疗作用 具有抗血管生成、抗炎、抗纤维化等功效。然而，有一些 没有FDA批准的针对湿性老年性黄斑变性的PPAR-α靶向药物。 第一阶段的拟议研究将集中于评估新型药物A91的体内疗效。 脉络膜新生血管模型中PPAR-α选择性激动剂的研究 湿性AMD的特点：血管生成异常、视网膜下炎症和纤维化。目标1将 A91能否抑制激光诱导的CNV体内脉络膜新生血管 模特。目的2检测PPAR-α对新生血管病变的抗炎和抗纤维化作用。 在成功证明其功效后，将建议进一步开展第二阶段研究。 A91可作为湿性AMD的潜在治疗药物。

PROJECT SUMMARY The aim of this proposal is to evaluate therapeutic potential of a novel PPAR-α agonist A91, for treating wet-form of age-related macular degeneration (wet-AMD). Current standard of care for wet-AMD, or other ocular diseases with an obvious dysfunctional microvasculature basis, is mainly dependent on managing the growth of abnormal blood vessels. In doing so, treatment options employ inherently invasive procedures challenged with technical limitations and financial constraints. For example, high cost, requirement of specialized facilities, repetitive intravitreal injections, and limited patient responsiveness are some of the critical barriers to progress in care for wet-AMD. Hence, developing small molecules designed for systemic administration will significantly improve various aspects of the current standard of care. As experimental evidence indicate, pharmacological activation of PPAR-α in various disease models exhibits therapeutic effects such as anti-angiogenic, anti-inflammatory and anti-fibrotic properties. However, there are no FDA-approved PPAR-α targeting drugs for wet-AMD. The proposed research in Phase I will focus on evaluating in vivo efficacy of A91, a novel PPAR-α selective agonist, in choroidal neovascularization (CNV) model by examining key aspects of wet-AMD: abnormal angiogenesis, subretinal inflammation and fibrosis. Aim 1 will study whether A91 can suppress choroidal neovascularization in vivo in a laser-induced CNV model. Aim 2 will test the anti-inflammatory and anti-fibrotic properties of PPAR-α on CNV lesions. Upon successful demonstration of its efficacy, Phase II studies will be proposed to further develop A91 as a potential therapeutic agent for wet-AMD.