A Small Molecule Targeting Wnt Pathway for Treatment of Diabetic Retinopathy

一种针对 Wnt 通路的小分子治疗糖尿病视网膜病变

• 批准号: 8250725
• 负责人: Danyang Chen
• 金额: $ 23.11万
• 依托单位: CHARLESSON, LLP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250725
• 关键词: Adverse effects; Adverse event; Animal Model; Animals; Attenuated; Biological Assay; Blindness; Blood Vessels; Clinical Trials; Complications of Diabetes Mellitus; Cultured Cells; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Disease Management; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Extravasation; FDA approved; Fibroblasts; Fibronectins; Fibrosis; Future; Gene Expression; Genes; Gold; Growth; Human; Inflammation; Intercellular adhesion molecule 1; Lead; Leukostasis; Ligands; Low-Level Laser Therapy; Measures; Modeling; Nuclear Translocation; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phosphorylation; Play; Procedures; Proteins; Public Health; Rattus; Recombinants; Research; Retina; Retinal; Role; Signal Transduction; Small Business Innovation Research Grant; Solid; Staging; Streptozocin; Synthesis Chemistry; Therapeutic; Toxicology; Tumor Necrosis Factor-alpha; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; angiogenesis; base; cell growth; connective tissue growth factor; cyclooxygenase 2; diabetic; diabetic patient; diabetic rat; improved; in vivo; inhibitor/antagonist; innovation; insight; intravitreal injection; laser photocoagulation; macular edema; novel; novel therapeutics; partial response; preclinical study; programs; proliferative diabetic retinopathy; retinal angiogenesis; small molecule; standard care

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness. This sight-threatening condition has become a public health challenge in the US. Currently, there is no FDA- approved drug for DR. Laser photocoagulation has remained the gold standard for the treatment of DR over the past two decades. However, laser therapy is usually applied for proliferative DR and is an invasive procedure with considerable limitations and side effects. Research efforts have increasingly focused on the application of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of DR. Recent clinical trials have shown that the therapy can slow or reverse the progression of DR, but many patients show only a partial response and the therapy results in adverse events. Due to the limited efficacy of both treatments, new drugs with higher efficacy are urgently needed to improve the management for DR. The Wnt pathway is involved in the multiple pathological processes, including angiogenesis, vascular permeability, inflammation and fibrosis, as it regulates many Wnt-responsive gene products which are known pathogenic factors in DR. Previous studies have shown that Wnt pathway is over-activated in the retinas of human patients with DR and in diabetic models. Further, blocking Wnt pathway by specific Wnt inhibitors down-regulated multiple pathogenic factors and ameliorated DR. These findings have established that the Wnt pathway over-activation induced by diabetes plays a key pathogenic role in DR. Thus, this pathway has become an attractive target of new drugs for the treatment of DR. Since Wnt inhibitors can simultaneously down-regulate multiple pathogenic factors, they should be more superior to anti-VEGF regents. In preliminary studies, we have screened over 100 novel, small molecule compounds to identify potent Wnt inhibitors by assessing their inhibitory effects on Wnt pathway and on retinal vascular endothelial cell growth. Compound E1086 was ultimately identified as a leading compound for blocking Wnt pathway. Our data showed that E1086 attenuated the Wnt pathway activation because it blocked LRP6 phosphorylation, an essential step in Wnt pathway activation, and enhanced 2-catenin phosphorylation to lead to 2-catenin degradation. The compound also inhibited Wnt3a (a Wnt ligand)-induced expression of multiple pathogenic factors. Moreover, E1086 specifically inhibited the growth of retinal vascular endothelial cells. However, it did not significantly inhibit the growth of primary pericytes and fibroblasts. Based on these observations, we hypothesize that E1086 has great potential to become an effective drug for the treatment of DR since it can inhibit retinal angiogenesis, vascular permeability, inflammation and fibrosis through targeting an upstream pathway. This SBIR Phase I project will serve as a proof-of-concept study to investigate the effects of E1086 on the Wnt pathway activation, retinal vascular leakage and inflammation in a diabetic animal model. The program includes two specific aims. The Aim 1 will determine the effect of E1086 on the Wnt pathway activation. The study will clarity the in vivo mechanisms of action of E1086 and will provide new insights into the rationale for the efficacy of E1086. The Aim 2 will evaluate the efficacies of E1086 on retinal vascular leakage and inflammation. The establishment of efficacy profile will direct the future preclinical studies of E1086. Applying an innovative strategy, this project will develop a new therapy with more effective than current medications to cure DR. The proposed studies will lay a solid groundwork for future Phase II preclinical studies of E1086. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness. There is no FDA-approved pharmacotherapy for DR and the current treatments are not effective in all DR patients. New drugs with higher efficacy are urgently needed to improve the management of this disease. This project will develop a new therapeutics which disrupts the multiple pathological processes though targeting Wnt pathway to cure DR.

描述（由申请人提供）：糖尿病性视网膜病（DR）是糖尿病的常见并发症，是失明的主要原因。在美国，这种威胁视力的状况已成为公共卫生挑战。目前，尚无FDA批准的DR药物。在过去的二十年中，激光光凝仍然是治疗DR的金标准。但是，通常将激光疗法用于增生性DR，是一种具有相当局限性和副作用的侵入性手术。研究工作越来越集中于抗血管内皮生长因子（VEGF）疗法用于DR的治疗。最近的临床试验表明，该疗法可以减慢或逆转DR的进展，但许多患者仅显示部分反应，而治疗会导致不良事件。由于两种治疗的疗效有限，因此迫切需要更高功效的新药来改善DR的管理。 Wnt途径参与了多种病理过程，包括血管生成，血管通透性，炎症和纤维化，因为它调节了许多WNT反应性基因产物，这些基因产物是DR中已知的致病因素。先前的研究表明，在患有DR和糖尿病模型的人类患者的视网膜中，Wnt途径过度激活。此外，通过特定的Wnt抑制剂阻止Wnt途径下调多个致病因素并改善DR。这些发现已经确定，糖尿病诱导的Wnt途径过度激活在DR中起关键的致病作用。因此，该途径已成为用于治疗DR的新药的吸引力。由于Wnt抑制剂可以同时下调多个致病因素，因此它们应该比抗VEGF摄政剂更优越。在初步研究中，我们通过评估其对Wnt途径和视网膜血管内皮细胞生长的抑制作用来筛选了100多种新型小分子化合物，以鉴定其有效的Wnt抑制剂。 Compound E1086最终被确定为阻断Wnt途径的领先化合物。我们的数据表明，E1086会减弱WNT途径的激活，因为它阻断了LRP6磷酸化，这是WNT途径激活的重要步骤，并增强了2-catenin磷酸化以导致2-catenin降解。该化合物还抑制了Wnt3a（Wnt配体）诱导的多种致病因素的表达。此外，E1086特别抑制了视网膜血管内皮细胞的生长。但是，它没有显着抑制原发性周细胞和成纤维细胞的生长。基于这些观察结果，我们假设E1086具有成为DR治疗的有效药物的巨大潜力，因为它可以通过靶向上游途径来抑制视网膜血管生成，血管通透性，炎症和纤维化。该SBIR I期项目将作为概念验证研究，以研究E1086对糖尿病动物模型中Wnt途径激活，视网膜血管泄漏和炎症的影响。该计划包括两个具体目标。目标1将确定E1086对Wnt途径激活的影响。该研究将清楚E1086的体内作用机理，并将为E1086功效的基本原理提供新的见解。 AIM 2将评估E1086对视网膜血管泄漏和炎症的效力。建立功效概况将指导E1086的未来临床前研究。采用创新策略，该项目将开发一种新的疗法，其比目前的药物更有效，以治愈DR。拟议的研究将为E1086的未来II期临床前研究奠定坚实的基础。 公共卫生相关性：糖尿病性视网膜病（DR）是糖尿病的常见并发症和失明的主要原因。没有FDA批准的DR药物疗法，目前的治疗在所有DR患者中都不有效。迫切需要具有更高功效的新药来改善该疾病的治疗。该项目将开发出一种新的治疗剂，该治疗疗法破坏了以Wnt途径为目标Cure DR的多个病理过程。