A Novel Small Molecule for The Prevention and Treatment of Age-Related Macular Degeneration

一种预防和治疗年龄相关性黄斑变性的新型小分子

• 批准号: 10325114
• 负责人: henry younghwa shin
• 金额: $ 27.73万
• 依托单位: EXCITANT THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325114
• 关键词: Affect; Age related macular degeneration; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Attenuated; Biological Products; Blindness; Blood; Blood Vessels; Blood-Retinal Barrier; CCL2 gene; Cells; Choroid; Choroidal Neovascularization; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Deterioration; Development; Disease; Dose-Limiting; Drusen; Elderly; Enzyme-Linked Immunosorbent Assay; Exhibits; Extravasation; Fenofibrate; Fluorescein Angiography; Future; Genes; HIF1A gene; Heart; In Vitro; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-6; Kidney; Lasers; Leukostasis; Ligands; Liver; Measures; Modeling; Mus; Oklahoma; Oral; Oral Administration; Oxidative Stress; PPAR alpha; Parents; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Prevention; Protein Isoforms; Research; Retina; Retinal Neovascularization; Retinal Pigments; Sclera; Signal Pathway; Solid; Specificity; Structure; Structure of retinal pigment epithelium; TNF gene; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; United States Food and Drug Administration; Universities; Vascular Endothelial Growth Factors; Virulence Factors; WNT Signaling Pathway; Western Blotting; amphiphilicity; analog; design; drug candidate; fluorescein isothiocyanate dextran; improved; intravitreal injection; laser photocoagulation; lipid metabolism; lipid transport; neovascular; neovascularization; novel; novel therapeutics; prevent; prospective; single molecule; small molecule; systemic toxicity; therapeutic target; transcription factor

SUMMARY Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the U.S. Wet AMD accounts for up to 90% of vision loss in AMD patients, which is characterized by choroidal neovascularization (CNV). Currently, no cure exists for AMD, and available drug therapies focus on intravitreal injection of anti- vascular endothelial growth factor (VEGF) agents. These anti-VEGF drugs have achieved impressive therapeutic effects on CNV in approximately 70% of AMD patients; however, the other 30% of patients remain unresponsive to anti-VEGF therapies. AMD is a multi-factorial disease，therapies that only target a single molecule (such as VEGF) do not benefit for all patients with AMD. Therefore, the development of new drugs to target multiple pathogenic factors with a single compound, is an unmet clinical need. Peroxisome proliferator-activated receptor α (PPARα) is a widely expressed, ligand-activated transcriptional factor. Recent studies provide strong evidence supporting that PPARα agonist could suppress the vicious cycle of chronic inflammation in the RPE and retina, a key cause in the pathogenesis of AMD. In addition, clinical studies have demonstrated that oral treatment of fenofibrate (an agonist of PPARα) could significantly reduce the need of laser photocoagulation for retinal neovascularization by 37-40%. PPARα agonist inhibits neovascularization and overproduction of multiple inflammatory factors in AMD animal models. Meanwhile, as small molecules, PPARα agonists can penetrate through the blood-retinal barrier, making it a promising novel oral option for the prevention and treatment of AMD. However, fenofibrate’s low specificity, low potency, and dose-limiting toxicities make it a non-ideal treatment option for AMD. Recently, our team has independently designed, synthesized, and screened more than 200 new PPARα agonists, from which we identified a novel non-fibrate compound A190, with significantly improved potency and selectivity for PPARα agonism (EC50 = ∼37 nM). It activates PPARα and upregulates expression of PPARα target genes in retinal cells, and confers anti-angiogenic and anti-inflammatory, and neuroprotective effects superior to fenofibrate. It also reduces retinal inflammation and vascular leakage in AMD models. We will evaluate the effects of A190 on retinal NV and inflammation in AMD animal models. The project will be achieved by two specific aims. Specific Aim 1: Determine whether A190 suppresses subretinal NV. Specific Aim 2: Determine whether A190 inhibits oxidative stress/inflammation. The proposed studies will prove the therapeutic effect of this compound on AMD models and will lay a solid ground for further PK, toxicity, mechanism studies in future Phase II project.

概括 与年龄相关的黄斑变性（AMD）是美国古老的失明的主要原因 占AMD患者视力丧失的90％，其特征是脉络膜新生血管化 （CNV）。目前，AMD尚无治愈 血管内皮生长因子（VEGF）剂。这些抗VEGF药物已获得令人印象深刻的疗法 大约70％的AMD患者对CNV的影响；但是，其他30％的患者仍然没有反应 进行抗VEGF疗法。 AMD是一种多因素疾病，仅针对单个分子（例如 VEGF）对所有AMD患者均不受益。因此，开发新药以靶向多种 具有单一化合物的致病因素是未满足的临床需求。过氧化物体增生剂激活受体 α（PPARα）是一个广泛表达的配体激活的转录因子。最近的研究提供了有力的证据 支持PPARα激动剂可以抑制RPE和视网膜中慢性感染的恶性循环， AMD发病机理的关键原因。此外，临床研究表明，口服治疗 非诺贝特（PPARα的激动剂）可以显着减少激光光凝的需求 新血管化37-40％。 PPARα激动剂抑制了多重的新血管形成和过量生产 AMD动物模型中的炎症因子。同时，作为小分子，PPARα激动剂可以穿透 通过血视网膜屏障，使其成为预防和治疗AMD的新型口服选择。 但是，非诺贝特表现的低特异性，低效力和限制剂量的毒性使其成为非理想的治疗 AMD的选项。最近，我们的团队已经独立设计，合成并筛选了200多个新的 PPARα激动剂，我们从中确定了一种新型的非纤维化化合物A190，并显着改善 PPARα激动剂的效力和选择性（EC50 = 〜37 nm）。它激活PPARα并更新表达式 视网膜细胞中的PPARα靶基因的，并承认抗血管生成和抗炎和神经保护作用 效果优于非诺贝特。它还减少了AMD模型中的残留感染和血管泄漏。我们将 评估A190对AMD动物模型中视网膜NV和炎症的影响。将实现该项目 通过两个具体的目标。特定目标1：确定A190是否抑制视网膜下NV。具体目标2： 确定A190是否抑制氧化应激/炎症。拟议的研究将证明治疗性 该化合物对AMD模型的影响，并将为进一步的PK，毒性，机制研究奠定坚实的基础 未来的II期项目。