Investigation of a first-in-class Frizzled4/LRP5 agonist in retinal disease models

在视网膜疾病模型中研究一流的 Frizzled4/LRP5 激动剂

基本信息

批准号：
10541901
负责人：
Stephane Angers
金额：
$ 45.36万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541901
关键词：
Active Biological Transport Agonist Anti-Inflammatory Agents Antibodies Biological Blood Blood Vessels Blood-Retinal Barrier Cells Characteristics Choroidal Neovascularization Coats&apos disease Complex Data Defect Development Diabetic Retinopathy Disease Disease model Endothelial Cells Extravasation Familial exudative vitreoretinopathy Fluorescence Microscopy Functional disorder Genes Growth Factor Hormones Human Human Engineering Immune Impairment In Vitro Inflammation Investigation Knowledge Laboratories Learning Ligands Low Density Lipoprotein Receptor Maintenance Mediating Metabolic Modality Modeling Mus Nature Nutrient Nutritional Requirements Pathogenicity Pathologic Pathway interactions Patients Pericytes Permeability Pharmaceutical Preparations Pharmacodynamics Population Proliferating Proteins Resistance development Retina Retinal Diseases Retinopathy of Prematurity Side Signal Induction Signal Transduction Structure-Activity Relationship System Telangiectasis Testing Therapeutic Translating Uveitis Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Vascularization WNT Signaling Pathway WNT7A gene angiogenesis beta catenin bevacizumab density drug candidate efficacy evaluation experimental study functional mimics in vivo Model lipoprotein receptor related protein 5 macula macular edema mouse model novel novel therapeutic intervention novel therapeutics prevent receptor response restoration single molecule solute transcriptomics virtual wasting

项目摘要

PROJECT SUMMARY/ABSTRACT The blood-retina barrier (BRB) protects the retina by limiting extravasation of solutes and immune cells and by providing active transport mechanisms for required nutrients and hormones. BRB dysfunction is implicated in retinal diseases including diabetic retinopathy, choroidal neovascularization, retinal occlusive diseases, uveitis, macular telangiectasia, familial exudative vitreoretinopathy, retinopathy of prematurity, and Coat’s disease. Although the key role of canonical Norrin and WNT7A/B signaling in inducing and maintaining blood-CNS barriers has been identified, highly potent and therapeutically amenable agonists of these pathways that could promote or restore BRB function are lacking. Signal initiation by Norrin requires the receptor Frizzled4 (FZD4) and two co-receptors, low-density-lipoprotein receptor-related protein 5 (LRP5) and tetraspanin-12 (TSPAN12). Here, we use an entirely novel agonist to activate canonical (i.e., beta-catenin-dependent) signaling in endothelial cells. The agonist is a human antibody modality that functionally mimics Norrin and WNT7A/B. The mechanism of action and its efficacy in distinct types of BRB defects are not known. We will conduct cell-based experiments to test the hypothesis that the agonist activates signaling by inducing complex formation of receptor and co-receptor molecules. To understand which types of BRB defects can be restored by the agonist, we will use multiple mouse models with BRB defects that have distinct characteristics. We will determine the efficacy in restoring the BRB in each model, perform transcriptomic experiments and immuno- histochemical analyses to identify mechanism of BRB restoration, and quantify vascular density. BRB defects, e.g., in macular edema, are treated with anti-VEGF or anti-inflammatory drugs. However, anti-VEGF therapies are not effective in all patients, and other patients may develop resistance. The novel agonist used here has an entirely different pharmacodynamic profile compared to anti-VEGF and anti-inflammatory drugs. Therefore, it is important to evaluate this drug candidate for its therapeutic potential.

项目概要/摘要血视网膜屏障（BRB）通过限制溶质和免疫细胞的外渗以及通过提供所需营养素和激素的主动运输机制与 BRB 功能障碍有关。视网膜疾病，包括糖尿病性视网膜病变、脉络膜新生血管、视网膜闭塞性疾病、葡萄膜炎、黄斑毛细血管扩张症、家族性渗出性玻璃体视网膜病变、早产儿视网膜病变和 Coat 病。尽管规范的 Norrin 和 WNT7A/B 信号在诱导和维持血液中枢神经系统 (CNS) 方面发挥着关键作用已经确定了障碍，这些途径的高效且可治疗的激动剂可以缺乏 Norrin 促进或恢复 BRB 功能的信号启动需要受体 Frizzled4 (FZD4)。以及两个辅助受体，低密度脂蛋白受体相关蛋白 5 (LRP5) 和 tetraspanin-12 (TSPAN12)。在这里，我们使用一种全新的激动剂来激活经典（即β-连环蛋白依赖性）信号传导激动剂是一种功能模仿 Norrin 和 WNT7A/B 的人类抗体形式。其作用机制及其对不同类型 BRB 缺陷的功效尚不清楚，我们将进行基于细胞的研究。实验检验激动剂通过诱导复合物形成来激活信号传导的假设受体和辅助受体分子了解哪些类型的 BRB 缺陷可以通过 BRB 修复。激动剂，我们将使用具有不同特征的 BRB 缺陷的多个小鼠模型。确定每个模型中恢复 BRB 的功效，进行转录组实验和免疫- 组织化学分析以确定 BRB 恢复机制并量化 BRB 缺陷。例如，对于黄斑水肿，可以使用抗 VEGF 药物或抗炎药物进行治疗。并非对所有患者都有效，其他患者可能会产生耐药性。此处使用的新型激动剂具有耐药性。与抗 VEGF 药物和抗炎药物相比，其药效学特征完全不同。评估该候选药物的治疗潜力非常重要。