Clinical translation of targeted intracoronary imaging for inflammatory activity

炎症活动性靶向冠状动脉内成像的临床转化

• 批准号: 10669761
• 负责人: Farouc Amin Jaffer
• 金额: $ 77.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669761
• 关键词: Amendment; Animal Model; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attenuated; Cardiac Catheterization Procedures; Carotid Endarterectomy; Cathepsins; Catheters; Cause of Death; Cells; Clinical; Clinical Research; Coronary; Coronary Arteriosclerosis; Coronary Thrombosis; Coronary artery; Coronary heart disease; Development; Devices; Diagnosis; Disease Management; Dose; Endothelium; Enzymes; Excision; Family suidae; Fiber; Fluorescence; Fluorescence Microscopy; Grant; Hemorrhage; Histology; Hour; Human; Image; Imaging Device; Imaging Techniques; Imaging technology; Immunohistochemistry; Inferior; Inflammation; Inflammatory; Injections; Intervention; Intravenous; Knowledge; Laboratories; Macrophage; Malignant Neoplasms; Mediating; Mediator; Methodology; Microanatomy; Molecular; Morbidity - disease rate; Multimodal Imaging; Mus; Myocardial Infarction; Near-infrared optical imaging; Operative Surgical Procedures; Optical Coherence Tomography; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathogenesis; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Process; RNA; Randomized; Reporting; Reproducibility; Research; Risk; Role; Safety; Saline; Severity of illness; Signal Transduction; Specimen; Stents; Structure; Subgroup; System; Technology; Testing; Three-Dimensional Image; Time; Transcript; Translating; Vascularization; Visualization; Work; acute coronary syndrome; advanced disease; atherogenesis; clinical imaging; clinical translation; coronary plaque; design; detection platform; digital; dosage; drug development; first-in-human; follow-up; high resolution imaging; imaging agent; imaging system; improved; in vivo; individual patient; inflammatory marker; innovation; intravital microscopy; mortality; multimodality; novel; optical spectra; percutaneous coronary intervention; pharmacologic; pre-clinical; prevent; progression risk; synergism; targeted agent; targeted imaging; thrombogenesis; tool

Inflammatory activity plays a major role in the development and progression of coronary artery disease (CAD), the major cause of mortality in the US and around the world. Until now, there has been no way to visualize and quantify coronary inflammation with the precision required to impact patient management. There is an opportunity for this capability gap to change, as a new clinical near-infrared fluorescence (NIRF) imaging agent called LUM015 has recently been introduced for cancer applications. LUM015 fluoresces following active cathepsin cleavage and thus appears promising as a highly specific targeted agent for inflammatory activity in atherosclerosis, as cathepsins are key mediators of plaque progression and coronary thrombosis risk. In this grant, we propose to investigate a first-in-human use of LUM015 NIRF for intracoronary CAD assessment. We will accomplish this objective by developing and clinically validating a multimodality imaging system and catheter that simultaneously obtains co-localized, intracoronary optical coherence tomography (OCT) images of lesional microanatomy and LUM015 NIRF to evaluate cathepsin-mediated plaque inflammatory activity. This technology will be clinically translated by investigating the targeting profile and dosing parameters for LUM015 in animal models of atherosclerosis and in humans undergoing carotid endarterectomy (Aim 1). Technology will be developed to spectrally unmix LUM015 NIRF from NIR autofluorescence (NIRAF) that is prevalent in advanced CAD (Aim 2.1). We also will advance NIRF-OCT technology by creating an innovative two-fiber catheter/rotary junction that removes fiber autofluorescence background. The resultant increase in LUM015 NIRF sensitivity will allow the time between injection and imaging to be minimized, which is important to capture many patients undergoing cardiac catheterization (Aim 2.2). The new catheter will also improve OCT image quality, which is inferior in current multimodality systems. After completion of Aims 1 and 2, the intravascular LUM015 NIRF-OCT technology will be tested in patients undergoing cardiac catheterization to show that NIRF- OCT can predict CAD severity (Aim 3). By establishing a new clinical imaging methodology for evaluating coronary microstructure and inflammatory activity in vivo, this work will have a major impact on CAD research, drug development, and personalized CAD management aimed at improving clinical outcomes.

炎症活动在冠状动脉疾病（CAD）的发展和发展中起主要作用， 美国和世界各地死亡的主要原因。到目前为止，一直没有可视化和 用影响患者管理所需的精度来量化冠状动脉炎症。有一个 作为新的临床近红外荧光（NIRF）成像剂的机会，这种能力差距会发生变化 最近引入了称为Lum015的癌症应用。 Lum015荧光荧光 组织蛋白酶的裂解，因此似乎有望成为高度特异的靶向药物，用于炎症活性 动脉粥样硬化，因为组织蛋白酶是斑块进展和冠状动脉血栓形成风险的关键介体。 在这笔赠款中，我们建议研究LUM015 NIRF的首次人类使用用于冠状动脉内CAD评估。 我们将通过开发和临床验证多模式成像系统和 同时获得共定位的冠状内光学相干断层扫描（OCT）图像的导管 病变的微解剖和Lum015 NIRF评估组织蛋白酶介导的斑块炎症活性。这 通过研究Lum015的靶向曲线和给药参数，将在临床上翻译技术 在动脉粥样硬化的动物模型中，在接受颈动脉内膜切除术的人类中（AIM 1）。技术将 从NIR自动荧光（NIRAF）开发为频谱的LUM015 NIRF（NIRAF） 高级CAD（AIM 2.1）。我们还将通过创建创新的两纤维来推进NIRF-OCT技术 去除纤维自动荧光背景的导管/旋转连接处。 LUM015的结果增加 NIRF敏感性将使注射和成像之间的时间最小化，这对于捕获很重要 许多接受心脏导管插入术的患者（AIM 2.2）。新导管还将改善OCT图像 质量，在当前的多模式系统中较低。 AIM 1和2完成后，血管内 LUM015 NIRF-OCT技术将在接受心脏导管插入术的患者中进行测试，以表明NIRF- OCT可以预测CAD的严重程度（AIM 3）。通过建立新的临床成像方法来评估 冠状动脉微观结构和体内炎症活动，这项工作将对CAD研究产生重大影响， 药物开发和个性化CAD管理旨在改善临床结果。