Small Molecule PPAR-alpha Agonism as a Novel Approach to Treat Eye Vascular Diseases

小分子 PPAR-α 激动剂作为治疗眼血管疾病的新方法

• 批准号: 10625310
• 负责人: Adam Scott Duerfeldt
• 金额: $ 38.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625310
• 关键词: Address; Affinity; Age related macular degeneration; Agonist; Angiogenesis Inhibitors; Animal Model; Antibodies; Apoptosis; Attenuated; Biochemical; Biological Assay; Biological Products; Blindness; Blood Vessels; Cell Culture Techniques; Cells; Cellular Assay; Clinical; Clinical Trials; Complement; Complex; Complications of Diabetes Mellitus; Data; Derivation procedure; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose Limiting; Down-Regulation; Drug Kinetics; Drug usage; Endothelium; Epidemic; Etiology; Exhibits; Extravasation; Eye; Fenofibrate; Financial Hardship; Genetic; Health Expenditures; Healthcare Systems; Human; Hyperlipidemia; Impairment; In Vitro; Inflammation; Inflammatory; Injections; Knowledge; Lead; Leukostasis; Lipids; Microsomes; Mitochondria; Modality; Modeling; Molecular; Nature; Nerve Degeneration; Operative Surgical Procedures; Oxidative Stress; PPAR alpha; Pathology; Patients; Pericytes; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Population; Population Growth; Prevalence; Prevention; Production; Property; Protein Isoforms; Public Health; Quality of life; Refractory; Research; Research Design; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Secondary to; Structure; Therapeutic; Toxic effect; Type 2 diabetic; United States; Vascular Diseases; Vascular Endothelial Growth Factors; Vision; aging demographic; aging demography; analog; attenuation; bevacizumab; burden of illness; clinically relevant; comorbidity; compliance behavior; design; diabetic; diabetic patient; efficacy evaluation; improved; in silico; innovation; lead optimization; meetings; mitochondrial dysfunction; neovascularization; neuroprotection; novel; novel strategies; novel therapeutics; patient population; pharmacologic; programs; prospective; protective effect; response; retinal toxicity; small molecule; standard of care; success; synergism; systemic toxicity; tool

Project Summary. Diabetic retinopathy (DR) is a common complication of diabetes and is the leading cause of blindness in the working population. Currently, >40% of the patient population fails to respond to gold-standard anti-VEGF direct intraocular injection treatments. New therapies that are superior to or synergistic with current approaches are of great value to patients. Unlike current treatment options, new approaches should be non- invasive (into the eye), affordable, and not reliant on specialized facilities. Our research program seeks to develop small molecule PPARα agonists as first-in-class treatments for DR. The promise of PPARα agonism as a novel strategy for treating DR has been confirmed in human clinical trials, wherein Fenofibrate (Feno), a clinically used drug for hyperlipidemia, exhibited robust protective effects against DR and retinal neovascularization (NV) in type 2 diabetic patients. We have determined that the protective effects of Feno are unrelated to its lipid-lowering activity, but rather result from its agonism of PPARα. Feno however, suffers from poor retinal distribution, low affinity/selectivity for PPARα, and chemotype related dose-limiting toxicities, all of which will limit its use as a DR therapy. Recently, we have identified a novel class of non-fibrate PPARα agonists that demonstrate improved potency and selectivity over Feno in vitro and exhibit efficacy in a retinal vascular leakage DR animal model (i.p. administration). All totaled, these data provide proof-of-concept and clearly demonstrate that 1) PPARα maintains critical roles in the major clinical features of DR and 2) Non-fibrate related PPARα agonists with improved physicochemical properties and ocular distribution have high promise to become first-in-class therapeutic options for DR. Specific Aims. (1) Structure-based hit to lead optimization of novel PPARα agonists; (2) Determine the potency and efficacy of newly designed and synthesized analogs; (3) Define the downstream molecular mechanism(s) underlying the protective effects of PPARα agonism against oxidative stress and inflammation in DR. Study Design. We will leverage in silico PPARα models developed in our lab to guide the design of improved agonists. Synthesized analogs will be assessed in in vitro biochemical and cellular assays for PPARα potency, level of agonism, and isoform selectivity. Compounds meeting pre-defined metrics will be advanced to secondary assays to determine anti-angiogenic, anti-oxidative, and neuroprotective effects in vitro. Top compounds will be assessed for efficacy against retinal leukostasis, endothelial impairment, pericyte loss, vascular leakage, visual function, and neuroretinal apoptosis in animal models. Top performing compounds will be utilized for detailed studies to define the downstream molecular mechanisms underlying the protective effects of PPARα agonism against the major etiological drivers of DR. The research is significant in that it will provide new therapeutic leads and a novel approach for the treatment of DR, thus addressing a pressing global need. The research is innovative in that it seeks to provide small molecule, non-invasive options for ocular conditions typically treated with destructive surgical procedures or intraocular injections of biologics.

项目总结。糖尿病视网膜病变（DR）是糖尿病的常见并发症，是导致糖尿病的主要原因