Translational Studies of AAV Gene Transfer for CHF

描述(由申请人提供)：50%的严重充血性心力衰竭(CHF)患者在症状出现后四年内死亡，尽管有最佳的治疗方法。心脏移植有80%的5年存活率，但在美国每年只有3000例心脏移植手术，500万患者患有心力衰竭。由于充血性心力衰竭的患病率正在增加，而且前景依然黯淡，我们需要新的方法来治疗充血性心力衰竭。胰岛素样生长因子-I(IGF-I)具有多效性，可能有益于衰竭的心脏。例如，由生长激素(GH)激活的IGF-I被认为可以增加心肌细胞的数量和大小，刺激血管生成，改善钙处理，并具有正性变力作用。尽管有这些假定的益处，但临床CHF中IGF-I/GH蛋白治疗的对照试验尚未成功，可能是由于IGF-I/GH的生物半衰期相对较短以及心脏中IGF-I/GH水平不足所致。我们预测，通过IGF-I的心脏基因转移，这种限制将被克服。自1993年以来，我们实验室在临床前和临床研究中使用了多种心脏基因转移方法。在拟议的研究中，我们将：1)使用适合治疗慢性CHF的长期表达载体，该载体可以轻松高效地部署；2)获得基因转录调控，使我们能够快速开启和关闭转基因表达；3)在严重CHF存在的情况下激活IGF-I转基因表达，以严格的方式测试疗效。最符合这些标准的载体是腺相关病毒(AAV)，它在冠状动脉内递送后在心脏中提供长期表达。TET调控系统将为控制转基因表达提供一种合适的手段。假设。激活IGF-I的表达将增加衰竭心脏的功能。目的1.研究心衰大鼠Aim 1A心脏基因转移及IGF-I表达的激活情况。确定疗效和作用机制目标1B：存活研究目标2.确定IGF-I表达的激活是否增加内皮前体细胞向衰竭的LV Aim的迁移3.评估心脏基因转移和IGF-I的激活在衰竭的猪心Aim 3A中的表达。确定大鼠冠状动脉内递送的最佳AAV载体。确定猪AIM 3C冠状动脉内注射的最佳AAV载体。确定冠状动脉内注射AAV.IGFI-tet治疗充血性心力衰竭的有效性和安全性这项拟议的研究旨在确定IGF-I表达增加对心力衰竭的有益影响的机制。我们还将确定IGF-I基因转移在啮齿动物和猪心力衰竭模型中的有效性和安全性。研究已经设计为能够在该奖项的5年期限内向FDA提交IND申请，以便启动针对CHF患者的IGF-I基因转移的临床试验。

DESCRIPTION (provided by applicant): Fifty percent of patients with severe congestive heart failure (CHF) die within four years of symptom onset despite optimal therapy. Heart transplantation has an 80% 5-year survival rate, but only 3000 are performed in the US each year, and 5 million patients have CHF. Because the prevalence of CHF is increasing, and the outlook remains dismal, we need new ways to treat CHF. Insulin-like growth factor-I (IGF-I) has pleiotropic effects that may benefit the failing heart. For example, IGF-I, which is activated by growth hormone (GH), is thought to increase cardiac myocyte number and size, stimulate angiogenesis, improve calcium handling and have positive inotropic effects. Despite these putative benefits, no controlled trial of IGF-I/GH protein treatment in clinical CHF has been successful, perhaps due to the relatively short biological half life of IGF-I/GH and insufficient levels in the heart. This limitation, we predict, will be overcome by cardiac gene transfer of IGF-I. Our laboratory has used a variety of cardiac gene transfer methods in preclinical and clinical studies since 1993. In the proposed studies we will: 1) Use a long-term expression vector suitable to treat chronic CHF, which can be easily and efficiently deployed; 2) Obtain regulation of gene transcription enabling us to turn on and off transgene expression quickly; 3) Activate IGF-I transgene expression in the presence of severe CHF to test efficacy in a stringent manner. The vector that will best fulfill these criteria is the adeno-associated virus (AAV), which provides long-term expression in the heart after intracoronary delivery. The tet-regulation system will provide a suitable means to control transgene expression. Hypothesis. Activation of IGF-I expression will increase function of the failing heart. Aim 1. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing rat heart Aim 1A. Determine efficacy and mechanisms for effects Aim 1B: Survival study Aim 2. To determine if activation of IGF-I expression increases endothelial precursor cell migration to the failing LV Aim 3. To evaluate cardiac gene transfer and activation of IGF-I expression in the failing pig heart Aim 3A. Identify optimal AAV vectors for intracoronary deliver in rats Aim 3B. Confirm optimal AAV vector for intracoronary delivery in pigs Aim 3C. Determine the efficacy and safety of intracoronary AAV.IGFI-tet in pigs with CHF The proposed research is designed to determine the mechanisms by which increased expression of IGF-I has beneficial effects on the failing heart. We also will determine the efficacy and safety of IGF-I gene transfer in rodent and pig models of CHF. Studies have been designed to enable filing an IND application with the FDA during the 5 year tenure of the award, so that clinical trials of IGF-I gene transfer in patients with CHF can be initiated.