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Proteolytic Imaging of Remodeling Myocardium

心肌重塑的蛋白水解成像

基本信息

批准号：
9138519
负责人：
FRANCIS G SPINALE
金额：
$ 29.41万
依托单位：
MICRO VIDE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-06 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9138519
关键词：
Acute myocardial infarction Address Affinity Animal Model Animals Binding Biodistribution Biological Biological Process Biology Businesses Cardiac Cause of Death Cicatrix Clinical Clinical Management Clinical Research Collaborations Development Diagnostic Drug Industry Enzyme Activation Enzymes Evaluation Extracellular Matrix Failure Family Family suidae Formulation Future Guidelines Hand Heart Heart failure Human Hybrids Image Image Analysis Imaging technology Industry Infarction Injury Isotopes Label Lead Left Left Ventricular Remodeling Licensing Malignant - descriptor Matrix Metalloproteinases Measures Medical Methods Modeling Molecular Target Monitor Morbidity - disease rate Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Outcome Pathway interactions Patients Peptide Hydrolases Perfusion Phase Preparation Procedures Process Production Proteolysis Protocols documentation Pump Radio Radiolabeled Reperfusion Therapy Risk Rodent Safety Severities Shapes Site Small Business Technology Transfer Research Specificity Stratification Structure Technology Technology Transfer Testing Thallium Therapeutic Therapeutic Agents Toxic effect Translating Treatment Efficacy United States Validation Ventricular X-Ray Computed Tomography abstracting adverse outcome clinical application clinically relevant commercialization companion diagnostics dosimetry drug discovery healthy volunteer heart function imaging agent improved in vivo industry partner injured interest man meetings mortality muscular structure novel novel therapeutics peptidomimetics pre-clinical prognostic programs public health relevance quantitative imaging radiotracer research clinical testing single photon emission computed tomography standard of care targeted imaging therapy development tool treatment strategy validation studies volunteer

项目摘要

DESCRIPTION (provided by applicant): Proteolytic Imaging of Remodeling Myocardium Abstract Heart attacks (i.e. myocardial infarction or MI) occur in more than 1.2 million patients annually. Advances in interventional and pharmacological therapies have dramatically improved survival following the initial MI, and patients are often surviving acute MI with more extensive myocardial injury. Consequently, the number of patients with previous MI continues to increase and as a result put in jeopardy millions of patients for development of heart failure an adverse outcome associated with extensive myocardial injury post-MI. In these patients with a previous MI, despite optimal standard-of-care, a scar can form in the portion of the heart muscle (myocardium) that was injured from the MI. Formation of a myocardial scar following MI is associated with a malignant remodeling process with respect to changes in the structure and shape of the MI region (infarct expansion), which is due to activation of enzymes that degrade key structures of the MI region - termed matrix metalloproteinases (MMPs). This adverse remodeling after MI can lead to increased morbidity and mortality in these patients. The development of new pharmacological / therapeutic approaches to target this process has been hampered by our ability to visualize and measure MMP activity in the heart of patients post-MI. The technology to be advanced in this application directly addresses this unmet medical need by developing a unique MMP targeted imaging agent that can be used in the clinical context of post-MI remodeling in patients, and thus move the entire field forward in terms of risk stratification and the evaluation of new therapies. This fast track technology transfer application is intended to move forward the MMP imaging technology by finalizing the formulation and validation of this approach in a clinically relevant preclinical large animal model of MI and then perform first in man safety and preliminary proof of concept studies. These studies will be undertaken in two phases. Phase I: standardize the synthesis and formulation of the radiolabeled MMP targeted imaging agent and perform initial toxicity studies in rodents. Phase II: perform in vivo serial MMP imaging and validate quantitative image analysis tools in an established preclinical large animal model of post-MI remodeling. Perform initial safety, biodistribution, and dosimetry studies in normal volunteers, and preliminary feasibility and proof of concept studies in patients post-MI through an Exploratory IND pathway, demonstrating that this technology would be highly relevant to identifying patients at increased risk for heart failur and as a companion diagnostic for the purposes of testing new drugs for reducing adverse post- MI remodeling.

描述（由申请人提供）：心肌重塑的蛋白水解成像摘要心脏病发作（即心肌梗死或MI）每年发生在120多万患者中。介入治疗和药物治疗的进步显著改善了初始MI后的生存率，患者通常在更广泛的心肌损伤下存活。因此，既往MI患者的数量持续增加，导致数百万患者处于心力衰竭的危险之中，心力衰竭是与MI后广泛心肌损伤相关的不良结局。在这些既往MI患者中，尽管采用了最佳标准治疗，但在MI损伤的心肌（心肌）部分仍可能形成瘢痕。MI后心肌瘢痕的形成与MI区域结构和形状变化（梗死扩大）相关的恶性重塑过程有关，这是由于降解MI区域关键结构的酶（称为基质金属蛋白酶（MMP））的活化所致。MI后的这种不良重塑可导致这些患者的发病率和死亡率增加。由于我们能够观察和测量MI后患者心脏中MMP活性，因此阻碍了针对该过程的新药理学/治疗方法的开发。该应用中的先进技术通过开发独特的MMP靶向成像剂直接解决了这一未满足的医疗需求，该成像剂可用于患者MI后重塑的临床背景，从而在风险分层和新疗法评价方面推动整个领域向前发展。这种快速技术转让申请旨在通过在临床相关的MI临床前大型动物模型中完成该方法的制定和验证，推进MMP成像技术，然后首先进行人体安全性和初步概念验证研究。这些研究将分两个阶段进行。第一阶段：标准化放射性标记MMP靶向显像剂的合成和制剂，并在啮齿动物中进行初步毒性研究。第二阶段：在已建立的MI后重塑的临床前大型动物模型中进行体内连续MMP成像并验证定量图像分析工具。在正常志愿者中进行初步安全性、生物分布和剂量测定研究，并通过探索性IND途径在MI后患者中进行初步可行性和概念验证研究，证明该技术与识别心力衰竭风险增加的患者高度相关，并作为伴随诊断用于检测新药以减少MI后不良重塑。