Localized Targeting of Matrix Proteases Following Myocardial Infarction

描述(申请人提供)：左心室(LV)重构是细胞和细胞外基质(ECM)事件的总和，通常发生在心肌梗死(MI)后，是临床结果的重要预测指标。细胞外基质蛋白水解酶的诱导增加，基质金属蛋白酶(MMPs)出现在MI后重塑的早期和晚期，MMPs的组织抑制物(TIMPs)失去内源性抑制控制被认为是这一过程中的一个生物学里程碑。尽管在心肌梗死后重塑的背景下，抑制基质金属蛋白酶仍然是一个重要的治疗目标，但全身应用广谱药理基质金属蛋白酶抑制剂可能与不良事件有关，这些担忧加上给药方案的困难，阻碍了临床进展。一种潜在的治疗途径尚未在翻译研究的背景下开发，那就是直接在重塑心肌梗死内局部注射TIMP。虽然已知有4种TIMP，但TIMP-3已被一致认为在心肌梗死后重塑的背景下降低。这项研究将验证一项中心假设，即靶向放置在MI区域内的聚合物-水凝胶提供连续的、局部的重组TIMP-3蛋白(rTIMP-3)释放，将降低总的MMP蛋白分解活性，稳定ECM，减少MI的扩张，并有利地影响LV的几何形状和功能。此外，使用一种可释放rTIMP-3的基质金属蛋白酶响应性聚合物-水凝胶结构，将提供一种新的、特异的方法来阻断细胞外基质的蛋白分解和抑制心肌梗死后的重塑。这些转化性研究将提供关于局部抑制基质金属蛋白酶对心肌梗死后重构的直接相关决定因素的有效性的关键功能和机制结果。这些研究将提供必要的临床前信息，以进一步推进局部基质金属蛋白酶抑制控制的治疗途径，以阻止心肌梗死后不利的左室重构和随后的心力衰竭发展的不可避免的进展。在这个国家，最常见的死亡和残疾原因之一是心脏病发作和随后的心力衰竭。心脏病发作后，现在清楚的是，MMPs的慢性激活继续侵蚀心脏ECM，最终导致心脏变形，导致扩张和向衰竭的过渡。这项研究将验证一种控制心脏病发作后MMPs的新疗法干预，从而开发出防止心脏病发作后患者进行性心肌重构的创新疗法。

DESCRIPTION (provided by applicant): Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI), and is an important predictor of clinical outcomes. Increased induction of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs) occur in the early and late phases of post-MI remodeling and a loss of endogenous inhibitory control by the tissue inhibitors of MMPs (TIMPs) has been identified as a biological milestone in this process. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens, have hindered clinical progress. One potential therapeutic avenue which has yet to be developed in a translational research context is the localized delivery of TIMPs directly within the remodeling MI. While there are 4 known TIMPs, TIMP-3 has been uniformly identified to be reduced in the context of post-MI remodeling. This study will test the central hypothesis that targeted placement of a polymer-hydrogel which provides continuous, localized release of recombinant TIMP-3 protein (rTIMP-3) within the MI region will reduce overall MMP proteolytic activity, stabilize the ECM, reduce MI expansion and favorably affect LV geometry and function. Moreover, using an MMP responsive polymer-hydrogel construct which will release rTIMP-3 in relation to net localized MMP proteolytic activity, will provide a novel and specific approach to interrupt ECM proteolysis and attenuate post-MI remodeling. These translational research studies will provide pivotal functional and mechanistic results regarding efficacy of localized MMP inhibition on directly relevant determinants of post-MI remodeling. These studies will provide the essential pre-clinical information necessary to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent development of heart failure. One of the most common causes of death and disability in this country is from a heart attack and the subsequent development of heart failure. Following a heart attack, it is now clear that chronic activation of MMPs continue to chew away at the heart ECM and eventually cause the heart to change shape, inducing dilation and the transition to failure. This study will validate a novel therapeuti intervention to control MMPs following a heart attack and thereby develop innovative treatments to prevent progressive myocardial remodeling in patients after a heart attack.