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.

项目摘要该建议的目的是评估新型PPAR-α激动剂A91的治疗潜力，以评估处理与年龄相关的黄斑变性（湿AMD）的湿式。当前的护理标准湿AMD或其他具有明显功能障碍微脉管系统的眼部疾病是主要取决于管理异常血管的生长。这样，治疗期权员工固有的侵入性程序受到技术限制和财务的质疑约束。例如，高成本，专业设施的要求，重复的玻璃体内注射和有限的患者反应能力是护理进展的一些关键障碍对于湿amd。因此，开发为全身管理设计的小分子将显着改善当前护理标准的各个方面。作为实验证据表明，在各种疾病模型中，PPAR-α的药物激活展示了治疗抗血管生成，抗炎和抗纤维化特性等作用。但是，有没有FDA批准的PPAR-α靶向湿AMD的靶向药物。拟议中的一期研究将重点放在评估A91的体内效率上，这是一种新颖的 PPAR-α选择性激动剂，脉络膜新生血管形成（CNV）模型，通过检查钥匙湿AMD的各个方面：异常血管生成，视网膜下注射和纤维化。目标1意志研究A91是否可以在激光诱导的CNV中抑制体内脉络膜新生血管化模型。 AIM 2将测试PPAR-α对CNV病变的抗炎和抗纤维化特性。成功证明了其有效性后，将提出II阶段研究以进一步发展 A91是湿AMD的潜在治疗剂。