Molecular Imaging of Ischemic Memory with Ultrasound - Transition to Humans

超声对缺血性记忆的分子成像 - 应用于人类

• 批准号: 7838481
• 负责人: Jonathan R Lindner
• 金额: $ 49.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7838481
• 关键词: Accident and Emergency department; Acute; Algorithms; Animal Disease Models; Applications Grants; Area; Blood Tests; Blood flow; Cardiovascular Diseases; Chest; Chest Pain; Clinical; Clinical Medicine; Clinical Trials; Coagulation Process; Complement; Contrast Media; Contrast echocardiography procedure; Coronary Arteriosclerosis; Coronary Occlusions; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dobutamine; Early Diagnosis; Echocardiography; Electrocardiogram; Evaluation; Functional disorder; Goals; Grant; Heart; Human; Image; Imaging Techniques; Imaging technology; Infarction; Injury; Intervention; Ischemia; Kidney; Laboratories; Lead; Life; Lung; Macaca mulatta; Manufacturer Name; Measurement; Measures; Medical Imaging; Memory; Metabolism; Methods; Microbubbles; Mind; Modeling; Molecular; Monoclonal Antibodies; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Necrosis; Oregon; Organ; Organ Transplantation; P-Selectin; P-selectin ligand protein; Pathway interactions; Patients; Pharmacology and Toxicology; Phase; Phase II Clinical Trials; Population; Preparation; Primates; Production; Protocols documentation; Radioisotopes; Recombinants; Reperfusion Injury; Research; Risk; Role; Safety; Sensitivity and Specificity; Serological; Signal Transduction; Skeletal Muscle; Spatial Distribution; Stress; Surface; Target Populations; Techniques; Testing; Time; Ultrasonography; United States Food and Drug Administration; Unstable angina; acute coronary syndrome; analog; base; diagnostic accuracy; efficacy testing; efficacy trial; hemodynamics; imaging probe; improved; molecular imaging; nonhuman primate; patient population; pre-clinical; public health relevance; pulmonary function; rapid diagnosis; safety testing; success; volunteer

DESCRIPTION (provided by applicant): Molecular imaging techniques with targeted imaging probes have been developed with specific clinical goals in mind. In cardiovascular disease, there is hope that molecular imaging will have a positive impact on patient management by early detection of disease or by increasing diagnostic accuracy for life-threatening illnesses. In patients who present with acute or recent chest pain but who have a non-diagnostic ECG, it may be possible to improve and expedite the diagnosis of acute coronary syndromes by imaging molecular alterations that occur with myocardial ischemia ("ischemic memory" imaging). This strategy is already being tested in clinical trials with metabolism-targeted radionuclide agents. A more rapid and portable approach would have practical advantages for evaluating these patients, most of whom are seen in the emergency department. We have developed ultrasound molecular imaging probes for detection of ischemia (with or without infarction) by targeting microbubble contrast agents to P-selectin. Ultrasound molecular imaging of P-selectin expression in murine models of brief ischemia detects the presence and extent of recent myocardial ischemia. We have recently developed an agent that is suitable for human use that is produced by conjugating a recombinant dimeric PSGL-1 analogue to microbubbles. The analogue alone is safe and is being tested in Phase-2 studies for amelioration of organ transplant injury. The purpose of this challenge grant is to transition molecular imaging technology for detection of recent ischemia into clinical trials. In preparation for this submission, arrangements have been made between our research group and a major contrast manufacturer (Bracco Imaging) for production of the agent in a GMP facility. We have four major milestones for this challenge grant proposal: (1) to test efficacy and safety of P-selectin targeted imaging in a non-human primate closed-chest model of brief myocardial ischemia; (2) to complete pharmacology/toxicology studies needed for Exploratory IND application; (3) to profile safety of the IND-approved agent in normal volunteers; and (4) to examine feasibility of imaging recent myocardial ischemia in stable patients immediately after primary percutanous intervention for acute coronary syndrome. These studies will provide necessary data for the development of a promising diagnostic approach to rapid diagnosis of patients with unstable angina and myocardial infarction, or for the detection of stress-induced ischemia in patients referred for non-invasive evaluation for coronary artery disease with stress or dobutamine echocardiography. PUBLIC HEALTH RELEVANCE: Current algorithms for the diagnosis of acute coronary syndromes (unstable angina and myocardial infarction) have major limitations leading to delayed or missed diagnosis. In this proposal, we will test the efficacy and safety of a new ultrasound targeted imaging technique that is able to detect molecular alterations in the small vessels of heart that occur during or after ischemia (low blood flow to the heart). The successful completion of our aims will lead to the development of a new strategy that can be used to more accurately diagnosis life-threatening coronary artery disease.

描述（由申请人提供）：靶向成像探针的分子成像技术已经开发出来，具有特定的临床目标。在心血管疾病中，分子成像有望通过早期发现疾病或提高对危及生命的疾病的诊断准确性，对患者管理产生积极影响。对于表现为急性或近期胸痛但心电图不可诊断的患者，可以通过心肌缺血时发生的分子改变成像（“缺血记忆”成像）来改善和加快急性冠状动脉综合征的诊断。这一策略已经在针对代谢的放射性核素制剂的临床试验中得到检验。一种更快速和便携的方法对评估这些患者有实际的优势，他们大多数在急诊科就诊。我们开发了超声分子成像探针，通过靶向微泡造影剂p -选择素来检测缺血（有或没有梗死）。p -选择素在小鼠短暂缺血模型中表达的超声分子成像检测近期心肌缺血的存在和程度。我们最近开发了一种适合人类使用的药物，它是通过将重组二聚体PSGL-1类似物与微泡偶联而产生的。单独的类似物是安全的，并且正在用于改善器官移植损伤的ii期研究中进行测试。这项挑战拨款的目的是将用于检测近期缺血的分子成像技术转化为临床试验。在准备提交这份报告的过程中，我们的研究小组与一家主要造影剂制造商（Bracco Imaging）就在GMP设施中生产造影剂做出了安排。我们有四个主要的里程碑：(1)在非人类灵长类动物短暂心肌缺血闭胸模型中测试p -选择素靶向成像的有效性和安全性；(2)完成探索性IND申请所需的药理学/毒理学研究；(3)分析ind批准的药物在正常志愿者中的安全性；(4)探讨经皮介入治疗急性冠状动脉综合征后立即对病情稳定的患者进行近期心肌缺血显像的可行性。这些研究将为开发一种有前景的诊断方法提供必要的数据，用于快速诊断不稳定型心绞痛和心肌梗死患者，或用于通过应激或多巴酚丁胺超声心动图进行无创评估的冠状动脉疾病患者的应激性缺血检测。