Cardiovascular Peptides and Myocardial Infarction

描述(申请人提供)：我们的目标是推进治疗急性心肌梗死(AMI)的创新蛋白质疗法，我们的目标是同时针对心脏和肾脏，以防止急性心肌梗死后的心肾重构和心力衰竭(HF)。我们的方法是基于这样的概念，即一种新型的Mayo工程鸟酰环化酶(GC)激活剂具有多效性的心肾保护特性，可以保护急性心肌梗死后的心肌和肾脏的结构和功能。我们的应用还提出了一种新的慢性多肽递送策略，这是优化蛋白质疗法抑制急性心肌梗死后心肾损害的关键。在实验性和人类急性心肌梗死中都提出了研究。我们的建议代表了一种先进的治疗策略，旨在通过使用第一个双GC受体嵌合NP(GC-B和GT；GC-A亲和力)来超越天然利钠肽(NPs)，该嵌合NP结合了来自GC-B激动剂CNP和GC-A激动剂DNP的关键氨基酸(AA)。CD-NP目前正在进行急性心力衰竭的临床试验，最近在正常志愿者身上完成了第一项人类研究。CD-NP是由申请人设计的，目的是利用CNP的特性，使CD-NP的降压作用低于BNP，并通过整合DNP的C端来具有增强肾脏、降低心脏前负荷和抑制RAAS的作用。我们的药物开发策略认识到由颗粒GC受体介导的内源性NPs的多效性，包括ANP和BNP结合的GC-A和CNP结合的GC-B。这些有益的特性包括利钠、血管松弛、抑制心肌细胞肥大和细胞凋亡、抑制纤维化、正性促血管生成和抑制肾素-血管紧张素-醛固酮(RAAS)。重要的是，我们在实验性和人类急性心肌梗死后的重塑中的应用超出了心脏的范围，而且还专注于肾脏，认识到急性心肌梗死后肾损伤对预后的重要性日益增加，这增加了未来发生心力衰竭的风险。具体目的1：探讨慢性皮下注射Cd-NP对实验性急性心肌梗死后心肾功能和结构的保护作用机制。假设：CD-NP具有抑制心肌梗死后心肾纤维化、减少心肌细胞凋亡、保护冠脉微血管容量、维持足细胞完整性和抑制醛固酮的作用。具体目标2：在一项概念验证的人类研究中确定CD-NP在人类急性心肌梗死中的安全性和心肾功能。假设：CD-NP是安全的，能激活血浆和尿液cGMP，抑制醛固酮，给药后1个月，将与心肾功能和结构的改善有关。因此，我们的建议的影响很大。具体地说，我们的方法促进了新药的开发和传递，目的是通过抑制急性心肌梗死后心脏的结构和功能损害来预防心力衰竭。此外，我们的高影响力急性心肌梗死后治疗策略也以肾脏保护为目标。最后，我们采取了一种高度平移的方法，结合了对实验性和人类急性心肌梗死的研究。

DESCRIPTION (provided by applicant): Our objective is to advance innovative protein therapeutics for acute myocardial infarction (AMI) in which we target both the heart and kidney with the goal of preventing post AMI cardiorenal remodeling and heart failure (HF). Our approach is built on the concept that a novel Mayo engineered guanylyl cyclase (GC) activator possesses pleuripotent cardiorenal protective properties, which preserves myocardial and renal structure and function following AMI. Our application also proposes a novel strategy for chronic peptide delivery, which is key in optimizing inhibition of post-AMI cardiorenal impairment by protein therapeutics. Studies are proposed in both experimental and human AMI. Our proposal represents an advanced therapeutic strategy designed to go beyond native natriuretic peptides (NPs) with the use of the first dual GC receptor chimeric NP (GC-B>GC-A affinity) that combines key amino acids (AA) from CNP, a GC-B agonist, and DNP, a GC-A agonist. CD-NP is now in clinical trials for acute HF following recent completion of a first in human study in normal volunteers. CD-NP was designed by the applicants to exploit characteristics of CNP so that CD-NP would be less hypotensive than BNP and possess renal enhancing, cardiac preload reducing and RAAS suppressing actions by integrating the C-terminus of DNP. Our drug development strategy recognizes the pleuripotent properties of the endogenous NPs, which are mediated by particulate GC receptors, which include GC-A to which ANP and BNP bind and GC-B to which CNP binds. These beneficial properties include natriuresis, vasorelaxation, inhibition of myocyte hypertrophy and apoptosis, suppression of fibrosis, positive lusitropism, angiogenesis and renin-angiotensin-aldosterone (RAAS) suppression. Importantly, our application in experimental and human post AMI remodeling goes beyond the heart and also focuses on the kidney recognizing the increasingly prognostic importance of post AMI renal injury which increases future risk for HF. Specific Aim 1: Determine cardiorenal protective mechanisms of chronic subcutaneous infusion of CD-NP in preserving cardiorenal function and structure post-experimental AMI. Hypothesis: CD-NP will suppress cardiorenal fibrosis, reduce myocyte apoptosis, preserve coronary microvascular volume, maintain podocytes integrity and inhibit aldosterone following AMI. Specific Aim 2: Define in a proof of concept human study the safety and cardiorenal actions of CD-NP in human AMI. Hypothesis: CD-NP will be safe, activate plasma and urinary cGMP, suppress aldosterone and one month following administration, will be associated with improved cardiorenal function and structure. Thus, the impact of our proposal is high. Specifically, our approach advances novel drug development and delivery, with the goal of preventing HF by suppressing post AMI structural and functional impairment of the heart. Further, our high impact post AMI therapeutic strategy also targets renal protection. Finally, we take a highly translational approach by combining studies of both experimental and human AMI.