Gene Transfer To Treat Heart Failure With Preserved Ejection Fraction

基因转移通过保留射血分数治疗心力衰竭

• 批准号: 9351275
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351275
• 关键词: Address; Aging; Animal Model; Award; Biodistribution; Cardiac; Cardiac Myocytes; Cardiovascular system; Cessation of life; Clinical Trials; Development; Diagnosis; Dose; EFRAC; Effectiveness; Functional disorder; Funding; Gene Transfer; Goals; Heart; Heart Rate; Heart failure; Hospitalization; Injection of therapeutic agent; Intravenous; Investigational Drugs; Investigational New Drug Application; Laboratories; Left; Left Ventricular Function; Life; Measures; Medical; Metabolic; Methods; Modeling; Mus; Myocardial Infarction; Office Visits; Oryctolagus cuniculus; Paper; Patients; Peptides; Phase; Physiologic intraventricular pressure; Physiological; Plasma; Prevalence; Problem Solving; Publishing; Safety; Sampling; Signal Transduction; Stress; Testing; Toxic effect; Ventricular; Virus; Work; adeno-associated viral vector; aged; base; blood pump; constriction; conventional therapy; expression vector; improved; intravenous injection; mortality; novel; novel therapeutics; paracrine; preclinical study; pressure; safety testing; tau Proteins; transgene expression; urocortin; vector

This proposal focuses on development of new potential treatments for patients with heart failure and preserved ejection fraction (HFpEF). Among symptomatic patients with HF, approximately half have preserved ejection fraction, and their mortality is similar to those with HF with reduced EF (HFrEF). However, unlike the case with HFrEF, there is currently no treatment for HFpEF that prolongs life, and few that reduce hospitalization rates for heart failure. We need new therapies to address this unmet medical need. Discovering and developing such an approach is the purpose of this proposal. Cardiovascular gene transfer is conceptually an attractive method for treating heart failure, 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 (IV) delivery of a long-term expression vector encoding a peptide, urocortin-2 (UCn2), with favorable cardiovascular effects through its paracrine action. A single intravenous injection in normal mice of an adeno-associated virus vector (AAV8) encoding murine UCn2 (AAV8.UCn2) has favorable effects on Tau and LV peak -dP/dt, two measures of left ventricular (LV) diastolic function. This approach solves the problem of attaining high yield cardiac gene transfer and ultimately would enable patients to be treated by intravenous injection during an office visit, and provides a novel means to increase diastolic function. The goal of this proposal is to test the safety and efficacy of this method of therapy in animal models of HFpEF. In the 4-year tenure of our present VA Merit, we have published three papers on the effectiveness of gene transfer of UCn2: one in normal mice, a second in mice with HFrEF, and a third that focuses on the safety and metabolic effects of UCn2 gene transfer. Gene transfer of AAV8 encoding UCn2 yielded persistent increases in plasma UCn2 (18 months following a single IV injection) and improved LV function in severe HF induced by myocardial infarction. In these studies, we noted that UCn2 gene transfer increased LV peak -dP/dt (p<0.0001) and reduced Tau (p=0.05). We now propose to test the safety and efficacy of IV delivery of AAV8.UCn2 in two models of HFpEF: 1) trans-aortic constriction (TAC), which imposes a LV pressure stress and HFpEF in the early phase; and 2) aged mice (18-months-old) many of which have diastolic dysfunction and meet criteria for HFpEF. Although our primary goal is to improve LV diastolic function and to test this in physiological studies after gene transfer, we also will determine mechanisms for the anticipated increase in diastolic function. In the final year, we will initiate testing in rabbits as a segue to an eventual Investigational New Drug (IND) application to initiate a clinical trial using AAV8.UCn2 to treat patients with HFpEF, a transition we have made in our laboratory twice previously (ClinicalTrials.gov: NCT00787059 and NCT00346437).

该提案重点是为心力衰竭患者开发新的潜在治疗方法 射血分数（HFPEF）。在有症状的HF患者中，大约一半保留了射血 分数及其死亡率类似于降低EF（HFREF）的HF的分数。但是，与情况不同 HFREF，目前没有延长寿命的HFPEF治疗，很少有降低住院率 为了心力衰竭。我们需要新的疗法来满足这种未满足的医疗需求。发现和开发这种 一种方法是该提议的目的。心血管基因转移在概念上是一种有吸引力的方法 以治疗心力衰竭，但难以以一种以一种方式获得高产量转基因在心脏中的表达 可以轻松，安全地应用是具有挑战性的。但是，我们最近证明了 静脉内（IV）递送编码肽2 （UCN2），通过其旁分泌作用具有良好的心血管效应。一次静脉注射 编码鼠UCN2（AAV8.UCN2）的腺相关病毒载体（AAV8）的正常小鼠具有优惠 对TAU和LV峰-DP/DT的影响，两种左心室（LV）舒张功能的测量。这种方法 解决获得高产量心脏基因转移的问题，并最终使患者成为 在办公室访问期间通过静脉注射治疗，并提供了增加舒张压的新颖手段 功能。该建议的目的是测试这种治疗方法在动物模型中的安全性和功效 HFPEF。 在我们目前VA功绩的4年任期中，我们发表了三篇有关基因有效性的论文 UCN2的转移：一只在正常小鼠中，第二秒在HFREF中，第三个重点是安全性和 UCN2基因转移的代谢作用。编码UCN2的AAV8的基因转移导致持续增加 血浆UCN2（一次静脉注射后18个月），并在严重HF中提高LV功能。 心肌梗塞。在这些研究中，我们注意到UCN2基因转移增加LV峰-DP/DT（p <0.0001） 并减少tau（p = 0.05）。现在，我们建议测试iV递送AAV8.UCN2的安全性和功效 HFPEF的模型：1）反式运动收缩（TAC），该收缩（TAC）施加了LV压力应力和HFPEF 早期； 2）年龄小鼠（18个月大），其中许多具有舒张功能障碍并符合标准 HFPEF。尽管我们的主要目标是改善LV舒张功能并在生理研究中进行测试 基因转移后，我们还将确定舒张功能预期增加的机制。在 最后一年，我们将在兔子中进行测试，作为最终调查新药（IND）的选择 使用AAV8.UCN2启动临床试验来治疗HFPEF患者的应用，我们已经进行了过渡 以前两次在我们的实验室中（ClinicalTrials.gov：NCT00787059和NCT00346437）。