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).

该提案的重点是为心力衰竭和保留的患者开发新的潜在治疗方法 射血分数（HFpEF）。在有症状的心力衰竭患者中，大约一半的射血功能得以保留 分数，其死亡率与 EF 降低的心力衰竭 (HFrEF) 患者相似。然而，与情况不同的是 HFrEF，目前尚无可延长生命的 HFpEF 治疗方法，也很少能降低住院率 用于心力衰竭。我们需要新的疗法来解决这一未满足的医疗需求。发现并开发这样的 一种方法是本提案的目的。心血管基因转移从概念上讲是一种有吸引力的方法 用于治疗心力衰竭，但难以以以下方式在心脏中获得高产率转基因表达： 能够轻松、安全地应用一直是一项挑战。然而，我们最近展示了 静脉内 (IV) 输送编码肽 urocortin-2 的长期表达载体的有效性 (UCn2)，通过其旁分泌作用具有良好的心血管作用。单次静脉注射 编码鼠UCn2（AAV8.UCn2）的腺相关病毒载体（AAV8）的正常小鼠具有良好的 对 Tau 和 LV 峰值 -dP/dt（左心室 (LV) 舒张功能的两项指标）的影响。这种做法 解决了获得高产量心脏基因转移的问题，并最终使患者能够 在就诊期间通过静脉注射进行治疗，并提供了一种增加舒张压的新方法 功能。该提案的目的是在动物模型中测试这种治疗方法的安全性和有效性 HFpEF。 在我们现任 VA Merit 的 4 年任期内，我们发表了三篇关于基因有效性的论文 UCn2 的转移：一个在正常小鼠中，第二个在 HFrEF 小鼠中，第三个侧重于安全性和 UCn2 基因转移的代谢效应。编码 UCn2 的 AAV8 基因转移产生了持续增加 血浆 UCn2（单次静脉注射后 18 个月）和改善 LV 功能 心肌梗塞。在这些研究中，我们注意到 UCn2 基因转移增加了 LV 峰值 -dP/dt (p<0.0001) 并减少了 Tau (p=0.05)。我们现在建议以两种方式测试 AAV8.UCn2 静脉注射的安全性和有效性 HFpEF 模型：1) 经主动脉缩窄 (TAC)，它在左心室施加压力，并在左心室施加 HFpEF 早期阶段； 2) 老年小鼠（18 个月大），其中许多具有舒张功能障碍并符合以下标准： HFpEF。尽管我们的主要目标是改善左心室舒张功能并在生理研究中对此进行测试 基因转移后，我们还将确定预期舒张功能增加的机制。在 去年，我们将开始在兔子身上进行测试，作为最终研究性新药 (IND) 的后续 申请启动使用 AAV8.UCn2 治疗 HFpEF 患者的临床试验，这是我们已经做出的转变 之前在我们的实验室进行过两次（ClinicalTrials.gov：NCT00787059 和 NCT00346437）。