Proteolytic Imaging of Remodeling Myocardium

 描述(由申请人提供)：重构心肌的蛋白分解成像每年有超过120万患者发生抽象心脏病发作(即心肌梗死或心肌梗死)。介入治疗和药物治疗的进步极大地提高了首次心肌梗死后的存活率，患者往往在急性心肌梗死后存活，并伴有更广泛的心肌损伤。因此，既往有心肌梗死的患者数量继续增加，从而使数百万患者面临发展为心力衰竭的危险，心力衰竭是与心肌梗死后广泛的心肌损伤相关的不良后果。在这些既往有心肌梗死的患者中，尽管有最佳的护理标准，但心肌梗死损伤的部分心肌(心肌)可能会形成疤痕。MI后心肌瘢痕的形成与MI区结构和形状的变化(梗塞扩大)有关的恶性重塑过程是由于降解MI区关键结构的酶的激活而引起的，称为基质金属蛋白酶(MMPs)。心肌梗死后的这种不良重塑可能导致这些患者的发病率和死亡率增加。针对这一过程的新的药物/治疗方法的发展一直受到我们观察和测量心肌梗死后患者心脏中基质金属蛋白酶活性的能力的阻碍。这项应用中的先进技术通过开发一种独特的基质金属蛋白酶靶向显像剂直接满足这一未得到满足的医疗需求，该显像剂可用于患者心肌梗死后重塑的临床背景，从而推动整个领域在风险分层和新疗法评估方面取得进展。这一快速通道技术转让应用程序 旨在通过在临床相关的临床前大型动物心肌梗死模型中最终完成这一方法的制定和验证，推动基质金属蛋白酶成像技术的发展，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：标准化放射性标记基质金属蛋白酶靶向显像剂的合成和配方，并在啮齿动物身上进行初步毒性研究。第二阶段：在已建立的心肌梗死后重构的临床前大动物模型中，进行体内连续的基质金属蛋白酶成像，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、生物分布和剂量学研究，并通过探索性IND途径对MI后患者进行初步的可行性和概念验证研究，表明这项技术将与识别心力衰竭风险增加的患者高度相关，并可作为辅助诊断，用于测试减少MI后不良重塑的新药。

 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.