Cardiovascular Peptides and Myocardial Infarction

描述（由申请人提供）：我们的目标是推进用于急性心肌梗死（AMI）的创新蛋白质疗法，我们的目标是心脏和肾脏，目的是预防AMI后心肾重塑和心力衰竭（HF）。我们的方法是基于一种新型梅奥工程的胍基环化酶（GC）激活剂具有多能性心肾保护特性的概念，该特性可以保护AMI后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肽递送策略，这是优化蛋白质治疗对ami后心肾损害抑制的关键。建议在实验和人类AMI中进行研究。我们的建议代表了一种先进的治疗策略，旨在超越天然利钠肽（NPs），使用第一个双GC受体嵌合NP （GC- b >GC- a亲和力），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衰的临床试验，最近在正常志愿者中完成了首次人体研究。CD-NP是申请人利用CNP的特点设计的，通过整合DNP的c端，使CD-NP具有比BNP更低的降压作用，并具有增强肾功能、降低心脏预负荷和抑制RAAS的作用。我们的药物开发策略认识到内源性NPs的多能性，这些NPs是由颗粒GC受体介导的，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尿钠、血管松弛、抑制心肌细胞肥大和凋亡、抑制纤维化、正性肌萎缩性、血管生成和肾素-血管紧张素-醛固酮（RAAS）抑制。重要的是，我们在实验和人类AMI后重构中的应用超越了心脏，还关注肾脏，认识到AMI后肾损伤的预后重要性日益增加，这增加了未来HF的风险。具体目的1：确定慢性皮下输注CD-NP对实验性AMI后心肾功能和结构的保护机制。假设：CD-NP可抑制心肾纤维化，减少心肌细胞凋亡，保持冠状动脉微血管体积，维持足细胞完整性，抑制心肌梗死后的醛固酮。具体目标2：在概念验证的人类研究中定义CD-NP在人类AMI中的安全性和心肾作用。假设：CD-NP是安全的，激活血浆和尿液cGMP，抑制醛固酮，并且在给药一个月后，将与改善心肾功能和结构相关。因此，我们的建议影响很大。具体来说，我们的方法推进了新型药物的开发和交付，目标是通过抑制AMI后心脏结构和功能损伤来预防HF。此外，我们的高影响AMI后治疗策略也针对肾脏保护。最后，我们通过结合实验和人类AMI的研究，采取高度转化的方法。

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. PUBLIC HEALTH RELEVANCE: There is a huge unmet need for new, safe and effective drugs to protect the heart and kidney after myocardial infarction so as to reduce the burden of heart failure. We have engineered a highly innovative designer peptide to preserve cardiorenal structure and function following myocardial infarction and now propose to advance this strategy in both experimental and human myocardial infarction including its chronic delivery by subcutaneous delivery.