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）：具有针对性成像探针的分子成像技术已开发出具有特定临床目标的靶标。在心血管疾病中，希望分子成像通过早期发现疾病或提高威胁生命的疾病的诊断准确性对患者管理产生积极影响。在出现急性或最近胸痛但具有非诊断性心电图的患者中，可以通过对心肌缺血（“缺血性记忆”成像）的分子改变来改善和加快急性冠状动脉综合症的诊断。该策略已经在具有代谢的放射性核素剂的临床试验中进行了测试。一种更快，更便携的方法将具有评估这些患者的实际优势，其中大多数在急诊科中看到了这些患者。我们已经开发了超声分子成像探针，用于通过将微气泡对比剂靶向P-选择素来检测缺血（有或没有梗塞）。短缺血的鼠模型中P-选择素表达的超声分子成像检测到最近的心肌缺血的存在和程度。我们最近开发了一种适用于人类使用的药物，该药物是通过将重组二聚体PSGL-1类似物结合到Microbubbles产生的。单独的模拟是安全的，并且正在2期研究中进行测试，以改善器官移植损伤。这项挑战的目的是转变分子成像技术，以将最近的缺血检测到临床试验中。为了准备此提交，我们的研究小组与主要的对比度制造商（BRACCO成像）进行了安排，用于在GMP设施中生产代理商。我们有四个主要的里程碑，这是这项挑战赠款提案：（1）在短暂心肌缺血的非人类灵长类动物闭合胸模型中测试P-选择蛋白靶向成像的功效和安全性； （2）完成探索性IND所需的药理学/毒理学研究； （3）在正常志愿者中介绍了折叠式代理的安全性； （4）检查急性冠状动脉综合征的原发性疗法干预后立即对稳定患者进行成像的可行性。这些研究将为开发一种有希望的诊断方法提供必要的数据，以快速诊断心绞痛和心肌梗塞患者的快速诊断，或者在检测患有抗炎动脉疾病的非侵入性评估的患者中检测胁迫性评估的患者胁迫或多丁胺疾病。 公共卫生相关性：当前用于诊断急性冠状动脉综合征的算法（不稳定的心绞痛和心肌梗塞）具有重大局限性，导致诊断延迟或错过。在此提案中，我们将测试一种新的超声靶向成像技术的功效和安全性，该技术能够检测出在缺血期间或缺血期间发生的小血管中的分子改变（低血流向心脏）。我们的目标的成功完成将导致一种新策略的发展，该策略可用于更准确地诊断威胁生命的冠状动脉疾病。