Gene Transfer To Treat Heart Failure With Preserved Ejection Fraction

这项建议的重点是开发新的潜在的治疗心力衰竭和保存的患者 射血分数(HFpEF)。在有症状的心衰患者中，大约有一半的患者保留了射血功能。 其死亡率与EF降低(HFrEF)的HF患者相似。然而，与以下情况不同 HFrEF，目前没有可以延长生命的HFpEF治疗方法，也很少有降低住院率的治疗方法 治疗心力衰竭。我们需要新的疗法来解决这一未得到满足的医疗需求。发现和发展这样的 这项提议的目的是采取一种方法。从概念上讲，心血管基因转移是一种有吸引力的方法 用于治疗心力衰竭，但难以在心脏中获得高产量的转基因表达， 能否方便、安全地使用一直是一项挑战。然而，我们最近演示了 静脉(IV)递送编码多肽Urocortin-2的长期表达载体的有效性 (UCn2)，具有良好的心血管作用，其旁分泌作用。一次静脉注射 编码小鼠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的影响，这是左室舒张功能的两个指标。这种方法 解决了获得高产量心脏基因转移的问题，最终将使患者能够 在办公室就诊时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。这项建议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。 在我们现任退伍军人事务部的四年任期内，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，第三个专注于安全性和 UCn2基因转移的代谢效应。编码UCn2的AAV8基因转移产生持续增加的 单次静脉注射18个月后血浆UCn2水平与重度心衰患者左心功能的改善 心肌梗死。在这些研究中，我们注意到UCn2基因转移增加了左心室峰值-dp/dt(p&lt；0.0001)。 降低Tau(p=0.05)。我们现在建议测试AAV8UCn2静脉注射的安全性和有效性 HFpEF模型：1)经主动脉缩窄(TAC)，在左心室内施加压力和HFpEF。 早期阶段；2)老年小鼠(18个月大)，其中许多有舒张期功能障碍，并符合 HFpEF。虽然我们的主要目标是改善左室舒张功能，并在生理学研究中测试这一点 在基因转移后，我们还将确定预期的舒张期功能增加的机制。在 最后一年，我们将启动在兔子身上的测试，作为最终研究新药(IND)的一部分 申请使用AAV8.UCn2治疗HFpEF患者的临床试验，这是我们已经取得的转变 在我们的实验室之前两次(ClinicalTrials.gov：NCT00787059和NCT00346437)。

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).