Proteomics of human vitreous to investigate mechanisms underlying the variability in anti-VEGF treatment response in neovascular AMD patients

人玻璃体蛋白质组学研究新生血管性 AMD 患者抗 VEGF 治疗反应差异的机制

• 批准号: 10673722
• 负责人: Milam A Brantley
• 金额: $ 17.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673722
• 关键词: Address; Aftercare; Age; Age related macular degeneration; Alternative Therapies; Angiogenic Proteins; Avastin; Blindness; Classification; Clinical; Clinical Data; Combined Modality Therapy; Consensus; Data; Development; Disease; Disease Progression; Dose; Elderly; Exudative age-related macular degeneration; Fundus; Guidelines; Human; Immunoassay; Inflammation; Inflammatory; Injections; Knowledge; Logistic Regressions; Measurement; Measures; Molecular; Optics; Outcome; Pathogenesis; Pathway interactions; Patients; Proteins; Proteomics; Resources; Retinal Diseases; Sampling; Technology; Testing; Time; Tomogram; Treatment Efficacy; Treatment Factor; Variant; Vascular Endothelial Growth Factors; Vision; Visual Acuity; angiogenesis; bevacizumab; blind; cohort; effective therapy; innovation; insight; neovascular; novel; personalized medicine; preservation; protein folding; protein function; repository; response; sex; standard of care; therapeutic target; treatment response; treatment strategy; trend; visual optics

PROJECT SUMMARY Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in older adults worldwide. Most vision loss in AMD is caused by the advanced neovascular form of the disease (NVAMD). Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are effective in preserving vision for many patients, but there is marked variability among NVAMD patients in treatment response. Molecular factors contributing to this variability in anti-VEGF response represent a critical gap in knowledge. Our proposal addresses this knowledge gap directly by leveraging a unique and powerful resource. We have an exclusive repository of deidentified vitreous samples collected in-office from more than 1,100 patients treated for retinal diseases, including many with NVAMD. We will couple this resource with a highly sensitive, high-throughput multiplex immunoassay-based proteomics technology to identify vitreous proteins associated with anti-VEGF treatment response in NVAMD. We hypothesize that variation in vitreous levels of inflammatory and angiogenic proteins impacts the fundamental mechanisms that underlie the variability in response to anti- VEGF treatment. To test this hypothesis, we will measure levels of proteins involved in inflammation and angiogenesis in vitreous samples collected from NVAMD patients both prior to and throughout the course of treatment. We have identified a cohort of 83 treatment-naïve NVAMD patients who received the standard three monthly loading doses of intravitreal bevacizumab, followed by monthly injections as needed based on visual acuity, fundus examination, and OCT assessment. Using visual acuity and OCT measurements, each patient’s primary (one month after three loading doses; Month 3) and secondary (6 months after treatment initiation; Month 6) anti-VEGF treatment responses were classified as Good, Partial, Poor, or Non-Response. In Aim 1, we will use Olink Proteomics’ multiplex immunoassays to measure levels of 733 proteins involved in inflammation and angiogenesis in vitreous samples collected from these NVAMD patients prior to their initial bevacizumab injection. To compare between Good+Partial Responders and Poor+Non-Responders, we will perform logistic regression of responder status (Good/Partial or Poor/Non-Response) against baseline levels of each protein with and without adjustment for covariates at both primary and secondary response timepoints. In Aim 2, we will determine the longitudinal bevacizumab-induced changes in vitreous levels of inflammatory and angiogenic proteins that correlate with clinical outcomes in NVAMD patients. For 58 of the patients from Aim 1, we have additional vitreous samples collected at Month 1 (one month after treatment initiation), Month 3, and Month 6. We will quantify levels of the same 733 inflammatory and angiogenic proteins in these longitudinal vitreous samples. We will compare the protein fold-changes and the trend of protein changes over time between Good/Partial Responders and Poor/Non-Responders at each response timepoint.

项目概要 年龄相关性黄斑变性 (AMD) 是老年人严重、不可逆视力丧失的主要原因 全世界成年人中大多数 AMD 视力丧失是由该疾病的晚期新生血管形式引起的。 （NVAMD）玻璃体内注射抗血管内皮生长因子（抗 VEGF）可有效保留。 许多患者的视力都有所下降，但 NVAMD 患者的治疗反应存在明显差异。 导致抗 VEGF 反应差异的分子因素代表了一个关键的知识空白。 我们的建议通过利用我们独特而强大的资源来直接解决这一知识差距。 拥有从 1,100 多名患者在诊室收集的未识别玻璃体样本的独家存储库 治疗视网膜疾病，包括许多患有 NVAMD 的疾病，我们将将此资源与高度敏感的、 基于高通量多重免疫分析的蛋白质组学技术来鉴定玻璃体相关蛋白 我们与 NVAMD 中的抗 VEGF 治疗反应作斗争。 和血管生成蛋白影响抗-反应反应变异性的基本机制 为了验证这一假设，我们将测量与炎症相关的蛋白质水平。 在治疗之前和整个过程中从 NVAMD 患者收集的玻璃体样本中进行血管生成 我们确定了一组 83 名未接受过治疗的 NVAMD 患者，他们接受了标准的三项治疗。 玻璃体内注射贝伐珠单抗的每月负荷剂量，然后根据视力情况每月注射一次 使用视力和 OCT 测量来评估每位患者的视力、眼底检查和 OCT 评估。 原发性（三次负荷剂量后一个月；第 3 个月）和继发性（治疗开始后 6 个月； 第 6 个月）抗 VEGF 治疗反应分为良好、部分、差或无反应。 在目标 1 中，我们将使用 Olink Proteomics 的多重免疫分析来测量所涉及的 733 种蛋白质的水平 在这些 NVAMD 患者初次接受治疗之前收集的玻璃体样本中的炎症和血管生成 为了比较良好+部分反应者和差+无反应者，我们将 根据基线水平对应答者状态（良好/部分或差/无应答）进行逻辑回归 每种蛋白质在主要和次要反应时间点进行或不进行协变量调整。 在目标 2 中，我们将确定贝伐单抗诱导的玻璃体水平的纵向变化 与 NVAMD 患者临床结果相关的炎症和血管生成蛋白。 来自目标 1 的患者，我们在第 1 个月（治疗后一个月）收集了额外的玻璃体样本 启动）、第 3 个月和第 6 个月。我们将量化相同 733 种炎症和血管生成蛋白的水平 我们将比较这些纵向玻璃体样品中的蛋白质倍数变化和蛋白质趋势。 在每个响应时间点，良好/部分响应者和差/无响应者之间随时间变化。