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: 10507176
• 负责人: Milam A Brantley
• 金额: $ 30.63万
• 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/10507176
• 关键词: Address; Aftercare; Age; Age related macular degeneration; Alternative Therapies; Angiogenic Proteins; Avastin; Blindness; 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; Variant; Vascular Endothelial Growth Factors; Vision; Visual Acuity; angiogenesis; base; 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

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.

项目摘要 与年龄相关的黄斑变性（AMD）是老年人严重，不可逆转视力丧失的主要原因 全球成人。 AMD中的大多数视力丧失是由疾病的晚期新生血管形式引起的 （NVAMD）。玻璃体内抗血管内皮生长因子（抗VEGF）注射可有效保存 许多患者的视力，但是NVAMD患者在治疗反应中的差异显着。 导致抗VEGF响应变异性的分子因素代表了知识的关键差距。 我们的建议通过利用独特而强大的资源来直接解决这一知识差距。我们 拥有从1,100多名患者的办公室收集的去识别的玻璃体样品的独家存储库 治疗残留疾病，包括许多NVAMD。我们将把这个资源与高度敏感的 高通量多重免疫测定蛋白质组学技术，以识别相关的玻璃体蛋白 NVAMD中的抗VEGF治疗反应。我们假设玻璃体炎症水平的变化 血管生成蛋白会影响基本机制，这些机制是响应抗 - VEGF治疗。为了检验这一假设，我们将测量参与炎症和 在整个过程中和整个过程中，从NVAMD患者收集的玻璃体样品中的血管生成 治疗。我们已经确定了有83例未接受治疗的NVAMD患者的队列，他们接受了三名 每月加载玻璃体内bevacizumab的剂量，然后根据视觉根据需要每月注射 敏锐度，眼底检查和OCT评估。使用视力和OCT测量值，每个患者的 初级（三个加载剂量后一个月；第3个月）和次级（治疗计划后6个月； 第6个月）抗VEGF治疗反应被归类为良好，部分，差或无响应。 在AIM 1中，我们将使用Olink蛋白质组学的多重免疫测定来测量涉及的733种蛋白质的水平 在这些NVAMD患者最初的玻璃体样品中的炎症和血管生成中 贝伐单抗注射。要比较好+部分响应者与差+非反应者之间的比较，我们将 对基线水平进行响应者状态（良好/部分或差/无响应）的逻辑回归 每种蛋白质在原发性和次要响​​应时间点上都没有调整的协变量。 在AIM 2中，我们将确定纵向贝伐单抗诱导的玻璃体变化的玻璃体变化 与NVAMD患者的临床结局相关的炎症和血管生成蛋白。 58 AIM 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品 启动），第3个月和第6个月。我们将量化相同733炎症和血管生成蛋白的水平 在这些纵向玻璃体样品中。我们将比较蛋白质褶皱变化和蛋白质的趋势 在每个响应时间点，良好/部分响应者与差/非反应者之间的随着时间的变化。