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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要糖尿病视网膜病变 (DR) 是糖尿病的常见并发症，也是糖尿病的主要原因。目前，超过 40% 的患者群体未能达到金标准。抗 VEGF 直接眼内注射治疗优于现有疗法或具有协同作用。与目前的治疗方案不同，新的方法应该是非非的。侵入性（进入眼睛）、负担得起且不依赖专门设施。开发小分子 PPARα 激动剂作为 DR 的一流治疗方法。一种治疗 DR 的新策略已在人体临床试验中得到证实，但非诺贝特 (Feno) 临床用于治疗高脂血症的药物，对DR和视网膜具有强大的保护作用我们已确定 Feno 对 2 型糖尿病患者的新生血管形成（NV）具有保护作用。然而，与其降脂活性无关，而是由于其对 PPARα 的激动作用。视网膜分布不良、对 PPARα 的亲和力/选择性低以及化学型相关的剂量限制毒性，所有这些这将限制其作为 DR 疗法的使用。最近，我们发现了一类新型非贝特 PPARα 激动剂。在体外表现出比 Feno 更高的效力和选择性，并在视网膜血管中表现出功效渗漏 DR 动物模型（腹腔注射给药）全部总计，这些数据提供了概念验证并清晰可见。证明 1) PPARα 在 DR 的主要临床特征中保持关键作用，2) 非贝特相关具有改善的理化性质和眼部分布的 PPARα 激动剂很有希望成为一流的 DR 治疗方案。具体目标 (1) 基于结构的靶向药物优化。 PPARα激动剂；（2）确定新设计和合成的类似物的效力和功效；（3）定义 PPARα激动剂抗氧化保护作用的下游分子机制我们将利用我们实验室开发的 PPARα 模型来研究压力和炎症。指导改进的激动剂的设计将在体外生化和细胞评估。检测 PPARα 效力、激动水平和异构体选择性，满足预先定义的指标。将进入二次测定以确定抗血管生成、抗氧化和神经保护作用将评估顶级化合物对视网膜白细胞停滞、内皮损伤、周细胞的功效。动物模型中表现最佳的化合物。将用于详细研究，以确定保护作用背后的下游分子机制 PPARα 激动剂对 DR 主要病因的影响该研究具有重要意义。为 DR 的治疗提供新的治疗线索和新方法，从而解决全球紧迫的问题该研究的创新之处在于它旨在为眼部提供小分子、非侵入性的选择。通常通过破坏性手术或眼内注射生物制剂来治疗的病症。