Translational Studies of AAV Gene Transfer for CHF

AAV 基因转移治疗 CHF​​ 的转化研究

• 批准号: 7380186
• 负责人: H. Kirk Hammond
• 金额: $ 34.63万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380186
• 关键词: Award; Biological; Calcium; Cardiac; Cardiac Myocytes; Chronic; Clinical; Clinical Research; Clinical Trials; Congestive Heart Failure; Dependovirus; Family suidae; Galactosidase; Gene Transfer; Genetic Transcription; Half-Life; Heart; Heart Transplantation; Insulin-Like Growth Factor I; Intravenous; Laboratories; Methods; Modeling; Numbers; Patients; Prevalence; Proteins; Rattus; Regulation; Research; Rodent; Safety; Somatotropin; Survival Rate; Sus scrofa; Symptoms; System; Testing; Tetanus Helper Peptide; Thinking; United States Food and Drug Administration; adeno-associated viral vector; angiogenesis; cell motility; design; expression vector; improved; pre-clinical; precursor cell; size; transgene expression; translational study; vector

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.

描述（由申请人提供）：50%的严重充血性心力衰竭（CHF）患者在症状发作后4年内死亡，尽管进行了最佳治疗。心脏移植的5年存活率为80%，但在美国每年仅进行3000例，500万患者患有CHF。由于CHF的患病率正在增加，前景仍然暗淡，我们需要新的方法来治疗CHF。胰岛素样生长因子-I（IGF-I）具有多效作用，可能有益于衰竭的心脏。例如，被生长激素（GH）激活的IGF-I被认为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肌力作用。尽管有这些假定的益处，但在临床CHF中没有IGF-I/GH蛋白治疗的对照试验成功，这可能是由于IGF-I/GH的生物半衰期相对较短且在心脏中的水平不足。我们预测，这种限制将通过IGF-I的心脏基因转移来克服。自1993年以来，我们的实验室在临床前和临床研究中使用了各种心脏基因转移方法。在所提出的研究中，我们将：1）使用适合于治疗慢性CHF的长期表达载体，其可以容易且有效地部署; 2）获得基因转录的调节，使我们能够快速打开和关闭转基因表达; 3）在严重CHF的存在下激活IGF-I转基因表达，以严格的方式测试功效。最能满足这些标准的载体是腺相关病毒（AAV），其在冠状动脉内递送后在心脏中提供长期表达。tet调节系统将提供控制转基因表达的合适手段。假说. IGF-I表达的激活将增加衰竭心脏的功能。目标1。目的：研究心力衰竭大鼠心脏Aim 1A基因转移及IGF-I表达的激活作用。确定疗效和作用机制目标1B：生存研究目标2。确定IGF-I表达的激活是否增加内皮前体细胞向衰竭LV Aim 3的迁移。目的：研究衰竭猪心Aim 3A中IGF-I基因的转移和激活。确定用于大鼠中冠状动脉内递送的最佳AAV载体目的3B。确认用于猪Aim 3C中冠状动脉内递送的最佳AAV载体。确定冠状动脉内AAV.IGFI-tet在患有CHF的猪中的有效性和安全性所提出的研究旨在确定IGF-1表达增加对衰竭心脏具有有益作用的机制。我们还将确定IGF-I基因转移在啮齿动物和猪CHF模型中的有效性和安全性。研究的目的是在该奖项的5年任期内向FDA提交IND申请，以便启动CHF患者中IGF-I基因转移的临床试验。