Gene Transfer To Treat Heart Failure With Preserved Ejection Fraction

该提案的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，大约一半的射血功能保留 其死亡率与EF降低的HF患者（HFrEF）相似。然而，与 HFrEF，目前没有延长生命的HFpEF治疗方法，也很少有降低住院率的方法 治疗心力衰竭我们需要新的治疗方法来解决这一未满足的医疗需求。发现和发展这样的 一种方法是本建议的目的。心血管基因转移在概念上是一种有吸引力的方法 但难以在心脏中获得高产转基因表达， 如何简单安全地应用一直是一个挑战。然而，我们最近已经证明， 静脉内（IV）递送编码肽尿皮质素-2的长期表达载体的有效性 （UCn 2），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UCn 2的腺相关病毒载体（AAV 8）（AAV8.UCn2）的正常小鼠具有良好的 对Tau和LV peak -dP/dt（左心室（LV）舒张功能的两个指标）的影响。这种方法 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 在门诊期间通过静脉注射治疗，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 的HFpEF。 在我们目前的VA Merit的4年任期内，我们发表了三篇关于基因治疗有效性的论文。 UCn 2的转移：一个在正常小鼠中，第二个在HFrEF小鼠中，第三个集中在安全性和 UCn 2基因转移的代谢效应。编码UCn 2的AAV 8的基因转移产生了持续的增加。 血浆UCn 2（单次IV注射后18个月）和改善LV功能 心肌梗死在这些研究中，我们注意到UCn 2基因转移增加了LV峰-dP/dt（p<0.0001）。 并降低Tau（p=0.05）。我们现在提出在两个受试者中测试AAV8.UCn 2的IV递送的安全性和功效。 HFpEF模型：1）经主动脉缩窄（TAC），其在左心室中施加压力应力和HFpEF。 早期;和2）老年小鼠（18个月大），其中许多具有舒张功能障碍，并符合 HFpEF。虽然我们的主要目标是改善左室舒张功能，并在生理学研究中进行测试， 基因转移后，我们还将确定预期的舒张功能增加的机制。在 最后一年，我们将开始在兔子身上进行试验，作为最终研究性新药（IND）的后续工作 申请启动使用AAV8.UCn 2治疗HFpEF患者的临床试验，这是我们已经完成的一个过渡 在我们的实验室两次（ClinicalTrials.gov：NCT 00787059和NCT 00346437）。

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).