Integrin-binding Peptide for Ocular Neovascularization and Macular Edema: Molecular Mechanism of Action

整合素结合肽治疗眼部新生血管和黄斑水肿：分子作用机制

基本信息

批准号：
10361561
负责人：
Peter A Campochiaro
金额：
$ 39.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361561
关键词：
Address Advanced Development Agonist Angiogenesis Inhibitors Angiogenic Peptides Angiopoietin-2 Angiostatins Binding Biomimetics Blindness Blood Vessels Cell Proliferation Characteristics Cicatrix Collagen Type IV Complex Data Disease Disease Progression Dissociation Dose Doxycycline Drug Kinetics Endostatins Endothelial Cells Extravasation Exudative age-related macular degeneration Eye Family Gel Goals Human Injections Insulin-Like-Growth Factor I Receptor Integrin Binding Intercellular Junctions KDR gene Maintenance Malignant neoplasm of brain Malignant neoplasm of lung Medical Methods Migration Assay Modeling Molecular Molecular Mechanisms of Action Mus Opsin Oryctolagus cuniculus Oxygen Patients Penetration Peptides Permeability Phosphorylation Photoreceptors Physiological Platelet-Derived Growth Factor beta Receptor Process Production Property Proteins Receptor Signaling Retina Retinal Diseases Retinal Vein Occlusion Sampling Series Signal Transduction Structure Systems Biology Testing Tetanus Helper Peptide Therapeutic Therapeutic Agents Time Tissues Transgenic Mice Transgenic Organisms Translating Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Visual Wild Type Mouse antagonist aqueous diabetic dimer disability experimental study in vivo inducible gene expression macular edema malignant breast neoplasm monomer mouse model multicatalytic endopeptidase complex neovascularization novel therapeutics ocular neovascularization peptidomimetics prevent receptor response retina blood vessel structure rho wound healing

项目摘要

Project Summary Endogenous protein inhibitors of neovascularization (NV) and vascular leakage have great potential as therapeutic agents for retinal and choroidal vascular diseases, but thus far that potential has not been realized partly because large proteins present challenges for manufacturing, maintenance of appropriate folding, and penetration into tissues. We have developed a collagen IV-derived 20-mer peptide mimetic, AXT107 that strongly suppresses ocular neovascularization and vascular leakage. Intravitreous injection of 1µg of AXT107 in mice has comparable activity to 40µg of aflibercept and when combined, activity is greater than with either alone. In rabbit eyes, 50µg AXT107 suppresses vascular leakage longer than 500µg aflibercept because it self-assembles into a gel depot in the vitreous cavity that provides sustained delivery to the retina. The goal of this proposal is to elucidate the mechanism of action of AXT107 and the mechanism by which it self-assembles into a gel depot which provides prolonged activity. Preliminary data show that AXT107 binds αvβ3 which disrupts signaling through VEGFR2. AXT107 also disrupts signaling through platelet-derived growth factor receptor β (PDGFRβ), c-Met, and insulin-like growth factor-1 receptor; we will test the hypothesis that these effects are also a consequence of αvβ3 binding. AXT107 binds α5β1 and activates Tie2 in the presence of Angiopoietin 2 (Angpt2). We will test the hypothesis that AXT107 binding dissociates α5β1 into monomers, thereby eliminating α5β1-induced constraint of Tie2 allowing it to translocate to cell junctions and form multimers that are activated by Angpt2 increasing junctional integrity. In mice with oxygen-induced ischemic retinopathy (OIR), we will test the hypothesis that high levels of Angpt2 which reduce the effects of the VEGF antagonist aflibercept, enhance the antiangiogenic and anti-permeability effects of AXT107 because in its presence Angpt2 is converted from a Tie2 antagonist to a Tie2 agonist. We will also test the hypothesis that AXT107 is superior to aflibercept + anti-Angpt2 because it does not depend solely on endogenous Angpt1 for Tie2 activation. The mechanism of AXT107 assembly and disassembly, and its effect on pharmacokinetics will be investigated. These studies will advance the development of AXT107 a novel therapeutic that combines two important activities, VEGF suppression and Tie2 activation, with prolonged duration of action, and thus addresses unmet medical needs for retinal and choroidal vascular diseases.

项目概要新血管形成（NV）和血管渗漏的内源性蛋白质抑制剂具有巨大的潜力视网膜和脉络膜血管疾病的治疗剂，但迄今为止其潜力尚未实现部分原因是大蛋白质对制造、适当折叠的维护和维护提出了挑战我们开发了一种 IV 型胶原蛋白衍生的 20 聚体肽模拟物 AXT107，玻璃体内注射 1μg AXT107 可强烈抑制眼部新生血管形成和血管渗漏。在小鼠中的活性与 40μg 阿柏西普相当，联合使用时的活性比任一药物都强在兔眼中，50μg AXT107 比 500μg 阿柏西普更能抑制血管渗漏，因为它自组装成玻璃体腔中的凝胶库，以持续输送至视网膜。该提案旨在阐明 AXT107 的作用机制及其自组装机制初步数据显示 AXT107 结合 αvβ3，从而提供持久的活性。 AXT107 会破坏通过 VEGFR2 的信号传导，也会破坏通过血小板衍生生长因子的信号传导。受体 β (PDGFRβ)、c-Met 和胰岛素样生长因子-1 受体；我们将检验这些假设效应也是 αvβ3 结合的结果，AXT107 结合 α5β1 并在存在 Tie2 的情况下激活 Tie2。我们将测试 AXT107 结合将 α5β1 解离为单体的假设，消除 α5β1 诱导的 Tie2 限制，使其易位至细胞连接处并形成 Angpt2 激活的多聚体可增加氧诱导缺血小鼠的连接完整性。视网膜病变 (OIR)，我们将检验以下假设：高水平的 Angpt2 会降低 VEGF 的作用拮抗剂阿柏西普，增强 AXT107 的抗血管生成和抗渗透作用，因为 Angpt2 的存在从 Tie2 拮抗剂转变为 Tie2 激动剂我们还将检验以下假设： AXT107 优于阿柏西普 + 抗 Angpt2，因为它不仅仅依赖于内源性 Angpt1 Tie2 激活。AXT107 组装和分解的机制及其对药代动力学的影响。这些研究将推动 AXT107 的开发，这是一种结合了两种药物的治疗小说。重要的活性，VEGF 抑制和 Tie2 激活，具有较长的作用持续时间，因此解决视网膜和脉络膜血管疾病未得到满足的医疗需求。