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.

项目总结