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

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.PROJECT NARRATIVE Age-related macular degeneration (AMD) is a common eye disorder in elderly population that affects nearly 196 million people worldwide. While several treatment options exist to control the principle hallmark of wet-AMD (i.e. abnormal blood vessel growth from the choroid), a large portion of patients receiving long-term anti-VEGF therapies (i.e. gold standard) still fail to maintain visual acuity, possibly owing to subretinal inflammation and fibrosis. Therefore, we propose to develop a novel therapeutic approach with complementarity and/or synergism to anti-VEGF therapies for a broader disease modification profile.