Urocortin 2 Gene Transfer for Heart Failure with Preserved Ejection Fraction

尿皮质素 2 基因转移治疗射血分数保留的心力衰竭

• 批准号: 10356056
• 负责人: H. Kirk Hammond
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356056
• 关键词: Address; Aging; Award; Ca(2+)-Transporting ATPase; Cardiac; Cardiac Myocytes; Cardiovascular system; Cessation of life; Clinical; Clinical Trials; Corticotropin-Releasing Hormone Receptors; Dahl Hypertensive Rats; Development; Diagnosis; Disease; EFRAC; Effectiveness; Endocrine; Endoplasmic Reticulum; Funding; Gene Transfer; Grant; Heart; Heart failure; Hypertension; Intravenous; Laboratories; Left; Left Ventricular Function; Life; Link; Maps; Measures; Medical; Membrane; Methods; Modeling; Mus; Pathway interactions; Patients; Peptides; Persons; Prevalence; Proteins; Rattus; Risk Factors; Safety; Sarcomeres; Series; Smooth Muscle; Testing; Time; Treatment Effectiveness; Vascular Smooth Muscle; Vasodilation; Vasodilator Agents; Ventricular; Veterans; Virus; Work; aged; base; blood pump; cardiovascular effects; clinical translation; conventional therapy; design; effectiveness evaluation; expression vector; heart function; heart preservation; hospitalization rates; hypertensive; improved; in vivo; mortality; mouse model; novel therapeutics; optimal treatments; paracrine; preclinical study; preservation; pressure; transgene expression; urocortin; vector

This proposal focuses on development of a new treatment for patients with heart failure and preserved ejection fraction (HFpEF). Among symptomatic patients with HF, half have HFpEF, and their mortality is similar to those with HFrEF. However, there are currently no treatments for HFpEF that prolong life, and few (if any) that reliably reduce HF hospitalization rates. We need new therapies to address this unmet medical need. Cardiovascular gene transfer is conceptually an attractive method for treating HF, but difficulty in obtaining high yield transgene expression in the heart in a manner that can be easily and safely applied has been challenging. However, we recently have demonstrated the effectiveness of intravenous (i.v.) delivery of a long-term expression vector (AAV8) encoding a peptide, urocortin 2 (Ucn2), which possesses favorable cardiovascular effects through its paracrine/endocrine actions. In our current VA Merit grant we have established the safety and efficacy of a 1-time i.v. administration of AAV8.Ucn2 in two murine models of HFpEF—aging and pressure overload, two risk factors for clinical HFpEF. However, there are several important issues that must be resolved prior to clinical translation of this much-needed therapy. Hypothesis: Ucn2/Ucn3 gene transfer, through paracrine/endocrine effects, will improve cardiac function and survival in two models of HFpEF (in different species) via corticotropin releasing hormone receptor 2 (CRHR2)-dependent enhancement of Ca2+ handling in cardiac myocytes Aim 1: To determine the effectiveness and survival advantage of Ucn2 vs Ucn3 gene transfer in a model of HFpEF due to hypertension (Dahl Salt-Sensitive Rat) Aim 2a: To determine if the beneficial effects of Ucn2 gene transfer on LV function in aged mice are abrogated by cardiac-targeted deletion of CRHR2 Aim 2b: To determine whether the beneficial effects of Ucn2 gene transfer on the aged LV result from enhanced Ca2+ handling and increased rates of sarcomere shortening and lengthening Aim 3: To determine the intracellular mechanisms linking Ucn2 and Ucn3 peptide activation of CRHR2 with enhanced Ca2+ handling in cultured cardiac myocytes These Aims are designed to answer key questions: 1) Will the benefits of Ucn2 gene transfer be seen in a second species in a second model of HFpEF (hypertensive Dahl Salt-Sensitive rats), will it confer a survival advantage, and will Ucn3 gene transfer have similar beneficial effects? These questions will be addressed in Aim 1; 2) To what degree are the beneficial effects of Ucn2 gene transfer due to cardiac CRHR2 activation vs systemic vasodilation due to activation of CRHR2 in smooth muscle and attendant systemic vasodilation? We will address this question by using cardiac-targeted deletion of CRHR2 (Aim 2); 3) Finally, we propose to map the intracellular pathways (mechanisms) from CM CRHR2 stimulation by Ucn2/Ucn3 to the predicted increase in Ca2+ handling in a series of studies conducted in isolated CMs (Aim 3). These preclinical studies, which are focused on mechanism of action and effectiveness of treatment in vivo will serve as a segue for an additional study in a large mammalian model of HFpEF under separate funding, and subsequently to the filing of an IND application for the initiation of a clinical trial, a transition we have made in our laboratory twice previously (ClinicalTrials.gov: NCT00787059 and NCT00346437).

该建议重点是为心力衰竭患者开发新的治疗方法 射血分数（HFPEF）。在有症状的HF患者中，一半患有HFPEF，其死亡率是 类似于HFREF。但是，目前尚无HFPEF的治疗方法可以延长寿命，并且 很少有（如果有）可靠地降低HF住院率。我们需要新的疗法来解决这个未定的 医疗需求。心血管基因转移在概念上是一种治疗HF的有吸引力的方法，但是 很难以一种可以轻松安全的方式获得心脏中高产量转化的表达 应用是挑战。但是，我们最近证明了静脉注射的有效性 （i.v.）递送编码肽2（UCN2）的长期表达载体（AAV8） 通过其旁分泌/内分泌作用具有有利的心血管效应。在我们目前的VA优点 授予我们已经建立了1次i.v.的安全性和效率aav8.ucn2二 HFPEF的鼠模型 - 临床HFPEF的两个风险因素。然而， 在此急需的临床翻译之前，必须解决几个重要问题 治疗。 假设：UCN2/UCN3基因转移，通过旁分泌/内分泌作用将改善心脏功能 以及通过皮质激素释放HORSENE的HFPEF（在不同物种中）的两种模型中的生存 接收器2（CRHR2） - 依赖于心肌细胞中Ca2+处理的增强 目标1：确定在模型中UCN2与UCN3基因转移的有效性和生存优势 由于高血压而引起的HFPEF（Dahl盐敏感大鼠） AIM 2A：确定UCN2基因转移对老年小鼠LV功能的有益影响是否是 由CRHR2的心脏针对心脏的删除 AIM 2B：确定UCN2基因转移对老年LV的有益作用是否由 增强的Ca2+处理和肌节缩短和延长的速率增加 目标3：确定连接UCN2和UCN3 CRHR2激活的细胞内机制 培养的心肌细胞中的Ca2+处理增强 这些目的旨在回答关键问题：1）UCN2基因转移的好处在 第二种模型的HFPEF（高血压DAHL盐敏感大鼠）中的第二种物种，它将符合生存 优势，UCN3基因转移会具有类似的有益作用吗？这些问题将被解决 在AIM 1中； 2）因心脏CRHR2引起的UCN2基因转移的有益效应在多大程度上 激活与全身性血管舒张，这是由于平滑肌和随之而来的全身性的CRHR2激活 血管舒张？我们将使用CRHR2的心脏针对性删除（AIM 2）来解决这个问题； 3）最后，我们建议通过CM CRHR2模拟的细胞内途径（机制）映射 在分离的CMS进行的一系列研究中，UCN2/UCN3在CA2+处理中预测的增加 （目标3）。这些临床前研究的重点是作用机理和有效性机理 体内的治疗将作为在大型HFPEF模型下进行额外研究的选择。 单独的资金，随后提交IND申请以启动临床试验的申请， 我们以前在实验室中进行了两次过渡（ClinicalTrials.gov：NCT00787059和 NCT00346437）。