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

评估新型 PPAR-a 激动剂对湿性 AMD 的治疗潜力

基本信息

批准号：
10081184
负责人：
henry younghwa shin
金额：
$ 27.29万
依托单位：
EXCITANT THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081184
关键词：
Affect Age related macular degeneration Agonist Angiography Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Blood Blood Vessels CCL2 gene Caring Choroid Choroidal Neovascularization Chronic Collaborations Collagen Type I Complex Development Disease Disease model Drug Screening Drug Targeting Elderly Exhibits Extravasation Eye diseases FDA approved Face Fatty Acids Fibronectins Fibrosis Fluorescein-5-isothiocyanate Formulation Foundations Gene Expression Gold Growth In Vitro Infiltration Inflammation Inflammatory Intercellular adhesion molecule 1 Intraperitoneal Injections Lasers Lead Lesion Ligands Liquid substance Measures Medical Mitochondria Modeling Modification Mus NF-kappa B Nuclear Receptors Oklahoma Optics PPAR alpha Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Population Procedures Property Research Research Personnel Retina Retinal Diseases Reverse Transcriptase Polymerase Chain Reaction Rodent Model Rogaine Series Solid Stains TNF gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Transportation Universities Vascular Endothelial Growth Factors Vision Visual Visual Acuity Visual impairment Western Blotting analog angiogenesis bevacizumab connective tissue growth factor cost design improved in vivo inflammatory marker intravitreal injection lipid metabolism macrophage mouse model neovascularization novel novel strategies novel therapeutic intervention outcome forecast oxidation patient response phase 2 study small molecule standard of care symptomatology synergism targeted treatment tomography treatment comparison

项目摘要

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.

项目概要本提案的目的是评估新型 PPAR-α 激动剂 A91 的治疗潜力，治疗湿性年龄相关性黄斑变性（湿性 AMD）的现行护理标准。湿性 AMD 或其他具有明显微血管功能障碍基础的眼部疾病主要依靠控制异常血管的生长来进行治疗。选项采用固有的侵入性程序，但受到技术限制和财务的挑战例如，成本高、需要专门的设施、重复的玻璃体内注射。注射和患者反应有限是护理取得进展的一些关键障碍因此，开发用于全身给药的小分子将成为可能。作为实验证据，显着改善当前护理标准的各个方面。表明，PPAR-α 在多种疾病模型中的药理激活具有治疗作用然而，也有抗血管生成、抗炎和抗纤维化等作用。目前尚无 FDA 批准的针对湿性 AMD 的 PPAR-α 靶向药物。拟议的 I 期研究将重点评估 A91 的体内功效，A91 是一种新型药物。 PPAR-α选择性激动剂，在脉络膜新生血管（CNV）模型中通过检查关键湿性AMD的方面：异常血管生成、视网膜下炎症和纤维化。研究 A91 是否可以在激光诱导的 CNV 体内抑制脉络膜新生血管形成目标 2 将测试 PPAR-α 对 CNV 病变的抗炎和抗纤维化特性。在成功证明其功效后，将提出 II 期研究以进一步开发 A91 作为湿性 AMD 的潜在治疗剂。