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: 10412945
• 负责人: Adam Scott Duerfeldt
• 金额: $ 43.54万
• 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/10412945
• 关键词: Address; Affinity; Age related macular degeneration; Agonist; 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; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose-Limiting; Down-Regulation; Drug Kinetics; Drug usage; Endothelium; Epidemic; Etiology; Exhibits; Extravasation; Eye; Fenofibrate; Financial Hardship; Genetic; Gold; Health Expenditures; Healthcare Systems; Human; Hyperlipidemia; Impairment; In Vitro; Inflammation; Inflammatory; Injections; Knowledge; Lead; Leukostasis; Lipids; Mitochondria; Modality; Modeling; Molecular; Nature; Nerve Degeneration; Operative Surgical Procedures; Oxidative Stress; PPAR alpha; Pathology; Patients; Pericytes; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Pharmacology; 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; analog; attenuation; base; bevacizumab; burden of illness; clinically relevant; comorbidity; compliance behavior; design; diabetic; diabetic patient; improved; in silico; innovation; lead optimization; meetings; mitochondrial dysfunction; neovascularization; novel; novel strategies; novel therapeutics; patient population; programs; prospective; protective effect; response; small molecule; standard of care; success; 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.

项目摘要。糖尿病视网膜病变（DR）是糖尿病的常见并发症，并且是糖尿病视网膜病变的主要原因。 劳动人口失明。目前，超过40%的患者对金标准治疗无效。 抗VEGF直接眼内注射治疗。上级或协同现有疗法的新疗法 这些方法对患者具有很大的价值。与目前的治疗方案不同，新的方法应该是非- 侵入性（进入眼睛），负担得起，不依赖于专门的设施。我们的研究计划旨在 开发小分子PPARα激动剂作为DR的一流治疗方法。 一种治疗DR的新策略已经在人类临床试验中得到证实，其中非诺贝特（Feno）， 临床上用于治疗高脂血症的药物，对DR和视网膜病变表现出强大的保护作用。 2型糖尿病患者的血管新生（NV）。我们已经确定Feno的保护作用是 与其降脂活性无关，而是由其对PPARα的激动作用引起。然而，费诺患有 视网膜分布差，对PPARα的亲和力/选择性低，以及化学型相关的剂量限制性毒性，所有这些 这将限制其作为DR治疗的使用。最近，我们发现了一类新的非贝特类PPARα激动剂， 其在体外表现出优于Feno改进的效力和选择性，并在视网膜血管中表现出功效， 渗漏DR动物模型（腹膜内给药）。总之，这些数据提供了概念验证， 证明1）PPARα在DR的主要临床特征中保持关键作用，2）非贝特类药物相关 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 针对DR特定目标的一流治疗选择。(1)基于结构的命中率优化 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激动剂对氧化应激的保护作用的下游分子机制 研究设计。我们将利用我们实验室开发的计算机模拟PPARα模型， 指导改进的激动剂的设计。合成的类似物将在体外生物化学和细胞生物学中进行评估。 测定PPARα效力、激动水平和亚型选择性。符合预定义指标的化合物 将进行二次试验，以确定抗血管生成，抗氧化和神经保护作用 体外将评估最佳化合物对视网膜白细胞停滞、内皮损伤、周细胞增殖、视网膜病变和视网膜病变的疗效。 损失，血管渗漏，视觉功能和神经视网膜细胞凋亡的动物模型。性能最佳的化合物 将用于详细的研究，以确定下游的分子机制，保护 PPARα激动剂对DR主要病因驱动因素的作用。该研究的重要性在于， 为DR的治疗提供了新的治疗线索和新的方法，从而解决了紧迫的全球性问题。 需要的这项研究是创新的，因为它旨在为眼部疾病提供小分子，非侵入性的选择。 通常用破坏性外科手术或眼内注射生物制剂治疗的病症。