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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。