Multimodal Molecular Imaging of Choroidal Neovascularization

脉络膜新生血管的多模态分子成像

• 批准号: 10736104
• 负责人: Yannis Mantas Paulus
• 金额: $ 67.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736104
• 关键词: Age related macular degeneration; Aging; Animal Model; Animals; Biological Markers; Biology; Blindness; Blood Vessels; Blood capillaries; Characteristics; Choroidal Neovascularization; Clinical assessments; Contrast Media; Development; Discipline; Disease; Ensure; Excretory function; Exhibits; Eye; Eye diseases; Fluorescence Microscopy; Functional Imaging; Goals; Histology; Image; Image Enhancement; Imaging technology; Immunohistochemistry; Integrin alphaVbeta3; Integrins; Legal Blindness; Light; Macular degeneration; Methods; Microscopy; Modeling; Molecular; Molecular Target; Monitor; Morphologic artifacts; Motion; Multimodal Imaging; Optical Coherence Tomography; Oryctolagus cuniculus; Pathologic; Patients; Peptides; Performance; Pharmacologic Substance; Population; Real-Time Systems; Renal clearance function; Research; Resolution; Safety; Scanning; Speed; System; Testing; Time; Toxic effect; United States; Urine; Vascular Endothelial Growth Factors; Visualization; Work; bevacizumab; biomaterial compatibility; clinically relevant; imaging biomarker; imaging modality; imaging platform; imaging system; improved; in vivo; invention; legally blind; matrigel; microscopic imaging; molecular imaging; molecular marker; multimodality; nanoGold; nanoparticle; non-invasive imaging; novel; novel therapeutics; pre-clinical; predicting response; prognostication; ranibizumab; real-time images; research and development; response; serial imaging; sound; subretinal injection; technology development; technology platform; temporal measurement; tool; translational impact; treatment response

PROJECT SUMMARY/ABSTRACT Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Choroidal neovascularization (CNV) is the leading cause of vision loss due to AMD. Although anti-vascular endothelial growth factor (VEGF) therapy has shown a great breakthrough in CNV treatment, persistent disease activity (PDA) is common. PDA has been demonstrated in 53% and 71% of patients treated monthly with ranibizumab and bevacizumab, respectively. 20% of patients become legally blind and another 30% suffer from some degree of vision loss after 5 years of anti-VEGF therapy. While AMD is a serious problem, one critical barrier limiting the ability to test novel therapies in preclinical settings is the lack of CNV animal models with PDA and the lack of methods for longitudinal monitoring of disease biomarkers and response to therapy. The goal of this project is to develop state-of-the-art multimodal molecular imaging for non-invasive and longitudinal assessment of the imaging biomarkers in a new CNV rabbit model with PDA to offer a platform technology for the development of novel therapeutics. We have developed a high resolution, multimodal ophthalmic imaging system incorporating photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence microscopy (FM). Novel chain-like gold nanoparticle clusters have been developed and used to enhance molecular imaging and target integrins present in CNV. We have also developed a robust animal model of PDA using older rabbits that demonstrate minimal response to anti-VEGF therapy. Encouraged by these exciting preliminary results, we propose to further develop this platform molecular imaging technology for AMD with a central hypothesis that a multimodal molecular imaging system that can evaluate the CNV animal model could contribute to understanding the fundamental biology of AMD and the development of new pharmaceutical therapies to treat CNV. We will test our hypothesis with the following Specific Aims: Aim 1: Upgrade the multimodal PAM, OCT, and FM system for real-time imaging in rabbit eyes. Aim 2: Test the prediction that young rabbits with robust response to anti-VEGF demonstrate capillary CNV while older rabbits demonstrate arteriolar CNV that can be visualized with multimodal imaging. Aim 3: Test the prediction that the rabbit models of CNV in response to anti- VEGF can be visualized at a molecular level with multimodal imaging powered by ultraminiature chain-like gold nanoparticles. The results of this work will include concepts, tools, and strategies for future research across several disciplines: a) Fundamental biology of AMD to visualize and quantify, with high spatial and temporal resolution, functional and molecular changes in living animals. b) Strategies for testing and developing novel drugs and non-pharmaceutical therapies in large eye models, particularly for CNV with PDA. c) Improved prognostication research to enable real-time molecular biomarkers of treatment response.

项目总结/摘要 湿性年龄相关性黄斑变性（AMD）是老年人不可逆失明的主要原因， 发达世界。脉络膜新生血管（CNV）是AMD导致视力丧失的主要原因。虽然 抗血管内皮生长因子（VEGF）疗法在CNV治疗中显示出巨大的突破， 持续性疾病活动（PDA）是常见的。在接受治疗的患者中，分别有53%和71%的患者出现PDA 每月分别用雷珠单抗和贝伐单抗。20%的患者成为法律上的盲人， 30%的患者在抗VEGF治疗5年后出现一定程度的视力丧失。虽然AMD是一个严重的问题， 限制在临床前环境中测试新疗法的能力的一个关键障碍是缺乏CNV动物 PDA模型和缺乏用于纵向监测疾病生物标志物和对 疗法该项目的目标是开发最先进的多模式分子成像，用于非侵入性 在新的患有PDA的CNV兔模型中纵向评估成像生物标志物，以提供平台 开发新疗法的技术。 我们已经开发了一种高分辨率，多模态眼科成像系统， 光声显微镜（PAM）、光学相干断层扫描（OCT）和荧光显微镜（FM）。 新型链状金纳米颗粒簇已经被开发并用于增强分子成像和 靶向CNV中存在的整合素。我们还用老年兔建立了一个可靠的动脉导管未闭动物模型， 显示对抗VEGF治疗的最小应答。在这些令人兴奋的初步结果的鼓舞下，我们 建议进一步开发用于AMD的平台分子成像技术，其中心假设是， 一种可以评估CNV动物模型的多模式分子成像系统可能有助于 了解AMD的基本生物学和开发新的药物疗法来治疗 CNV.我们将通过以下具体目标来检验我们的假设：目标1：升级多模式PAM、OCT， 和FM系统进行兔眼实时成像。目的2：检验幼兔健壮性的预测 对抗VEGF的反应显示毛细血管CNV，而老年兔显示小动脉CNV， 通过多模式成像可视化。目的3：验证抗-CNV抗体对兔CNV模型的预测作用。 VEGF可以在分子水平上通过超微型链状金提供动力的多模式成像进行可视化 纳米粒子这项工作的结果将包括未来研究的概念、工具和策略 a）AMD的基础生物学，以可视化和量化，具有高的空间和时间 分辨率，功能和分子变化在活体动物。B）测试和开发新的 药物和非药物疗法在大眼睛模型中的应用，特别是对于伴有PDA的CNV。（c）改进 验证研究，以实现治疗反应的实时分子生物标志物。