Cardiovascular Peptides and Myocardial Infarction

描述（由申请人提供）：我们的目标是推进急性心肌梗死（AMI）的创新蛋白质治疗，其中我们靶向心脏和肾脏，目的是预防AMI后心肾重塑和心力衰竭（HF）。我们的方法是建立在一种新的马约工程鸟苷酸环化酶（GC）激活剂具有多功能的心肾保护特性，保护心肌和肾脏的结构和功能后AMI的概念。我们的申请还提出了一种用于长期肽递送的新策略，这是通过蛋白质治疗优化AMI后心肾损害抑制的关键。在实验和人类AMI中提出了研究。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（NP），使用第一种双GC受体嵌合NP（GC-B>GC-A亲和力），其组合了来自CNP（GC-B激动剂）和DNP（GC-A激动剂）的关键氨基酸（AA）。在最近完成了在正常志愿者中的首次人体研究后，CD-NP现在处于急性HF的临床试验中。CD-NP由申请人设计以利用CNP的特征，使得CD-NP将比BNP具有更小的扩张性，并且通过整合DNP的C末端而具有肾增强、心脏前负荷降低和RAAS抑制作用。我们的药物开发策略认识到内源性NP的多能性，其由颗粒GC受体介导，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、血管舒张、抑制肌细胞肥大和凋亡、抑制纤维化、正向肌萎缩、血管生成和抑制肾素-血管紧张素-醛固酮（RAAS）。重要的是，我们在实验和人类AMI后重塑中的应用超出了心脏，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。具体目标1：确定慢性皮下输注CD-NP在保护实验性AMI后心肾功能和结构方面的心肾保护机制。假设：CD-NP可抑制AMI后心肾纤维化，减少心肌细胞凋亡，保护冠状动脉微血管容积，维持足细胞完整性，抑制醛固酮。具体目标2：在概念验证人体研究中确定CD-NP在人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cGMP，抑制醛固酮，给药一个月后，将与改善心肾功能和结构有关。因此，我们的建议的影响是很大的。具体而言，我们的方法推进了新药开发和递送，目的是通过抑制AMI后心脏的结构和功能损伤来预防HF。此外，我们的高影响力AMI后治疗策略还针对肾脏保护。最后，我们采取了高度转化的方法，结合实验和人类AMI的研究。 公共卫生相关性：对于新的、安全的和有效的药物存在巨大的未满足的需求，以在心肌梗死后保护心脏和肾脏，从而减轻心力衰竭的负担。我们已经设计了一种高度创新的设计肽，以保护心肌梗死后的心肾结构和功能，现在提出在实验和人类心肌梗死中推进这种策略，包括通过皮下递送的慢性递送。

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.