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）：具有靶向成像探针的分子成像技术已经开发出特定的临床目标。在心血管疾病中，分子成像有望通过早期发现疾病或提高危及生命疾病的诊断准确性，对患者管理产生积极影响。对于出现急性或近期胸痛但心电图无法诊断的患者，通过对心肌缺血时发生的分子改变进行成像（“缺血记忆”成像）可能会改善和加快急性冠状动脉综合征的诊断。该策略已经在针对代谢的放射性核素药物的临床试验中进行了测试。更快速、更便携的方法对于评估这些患者具有实际优势，其中大多数患者都在急诊科就诊。我们开发了超声分子成像探针，通过将微泡造影剂靶向 P-选择素来检测缺血（有或没有梗塞）。短暂缺血小鼠模型中 P-选择素表达的超声分子成像可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试剂，它是通过将重组二聚体 PSGL-1 类似物与微泡缀合而产生的。单独的类似物是安全的，并且正在二期研究中进行测试，以改善器官移植损伤。这项挑战资助的目的是将用于检测近期缺血的分子成像技术转变为临床试验。为准备本次提交，我们的研究小组和一家主要造影剂制造商（Bracco Imaging）已做出安排，在 GMP 设施中生产该试剂。对于这项挑战拨款提案，我们有四个主要里程碑：（1）在非人灵长类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) 检查在急性冠脉综合征初次经皮介入治疗后立即对稳定患者进行近期心肌缺血成像的可行性。这些研究将为开发一种有前途的诊断方法提供必要的数据，以快速诊断不稳定型心绞痛和心肌梗塞患者，或用于通过应激或多巴酚丁胺超声心动图对转诊进行非侵入性冠状动脉疾病评估的患者检测应激性缺血。 公共卫生相关性：当前诊断急性冠脉综合征（不稳定型心绞痛和心肌梗死）的算法存在重大局限性，导致诊断延迟或漏诊。在这项提案中，我们将测试一种新的超声靶向成像技术的有效性和安全性，该技术能够检测缺血期间或之后发生的心脏小血管的分子变化（心脏血流量低）。我们目标的成功实现将导致开发一种新策略，可用于更准确地诊断危及生命的冠状动脉疾病。