Gene transfer during LVAD support

LVAD 支持期间的基因转移

• 批准号: 6666442
• 负责人: ARTHUR M FELDMAN
• 金额: $ 29.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666442
• 关键词: adeno associated virus group; auxiliary heart prosthesis; baboons; biotechnology; clinical research; cooperative study; gene therapy; growth factor receptors; heart failure; human subject; medical implant science; receptor expression; transfection /expression vector; tumor necrosis factor alpha

Heart failure secondary to systolic dysfunction is a disease of epidemic proportions in the U.S. Although medical therapy can prolong survival, decrease hospitalization, and alleviate symptoms, the disease is progressive and many patients eventually present with fulminant and/or unremitting symptoms. In this group of patients, left ventricular assist devices (LVADs) have been utilized to "bridge" patients between LVAD implantation and cardiac transplantation. Interestingly, in a subset of patients, the LVAD can be weaned over time, leading investigators to hypothesize that LVAD support might enable patients to be "bridge to recovery" Indeed, studies have demonstrated salutory changes in myocyte function after chronic LVAD support. However, LVAD supported hearts also demonstrate increased fibrosis, apoptosis, and extracellular matrix remodeling. These reports led us to speculate that therapeutic interventions directed at inhibiting matrix remodeling might improve the ability to wean patients from LVAD support. During the past 5 years, we have demonstrated that the pro-inflammatory cytokine tumor necrosis factor (TNF) plays an important role in the development of the end-stage heart failure phenotype. Infusions of TNF or over-expression of TNF in animal models induces cardiac dilitation, diminished cardiac contractility, fibrosis, and extracellular matrix remodeling: changes that can be reversed by treatment with TNF soluble receptor (sTNFR). Indeed, systemic administration of sTNFR has demonstrated benefits in patients with symptomatic heart failure. As TNF is expressed at high levels in the LVAD supported heart, we hypothesized that treatment with sTNFR would substantially improve the ability to bridge patients to recovery and LVAD weaning. Unfortunately, systemic administration of TNFR is problematic in LVAD supported hearts because of the inherent risk of infection in these patients and the important role of TNF in the immune response. Thus, we hypothesized that direct injection of the heart muscle with an adeno- associated virus (AAV) driving sTNFR expression would have salutory effects. Studies in our own laboratory have demonstrated that AAV vectors: 1) are non-immunogenic; 2) provide persistent expression in muscle; and 3) can be constructed with cardiac specific and tetracycline- responsive promoters. Accordingly, this application will test the hypothesis that direct intramyocardial injection of AAV-sTNFR at the time of LVAD implantation could effect adaptive changes in the heart that could facilitate the ability to wean failing hearts from LVAD support.

在美国，继发于收缩功能障碍的心力衰竭是一种流行性疾病。尽管药物治疗可以延长生存期、减少住院治疗并缓解症状，但该疾病是进行性的，许多患者最终出现暴发性和/或持续性症状。在这组患者中，左心室辅助装置（LVAD）已被用于“桥接”LVAD植入和心脏移植之间的患者。有趣的是，在一部分患者中，LVAD可以随着时间的推移而脱机，导致研究人员假设LVAD支持可能使患者成为“恢复的桥梁”。然而，LVAD支持的心脏也表现出增加的纤维化、细胞凋亡和细胞外基质重塑。这些报告使我们推测，针对抑制基质重塑的治疗干预可能会提高患者脱离LVAD支持的能力。在过去的5年中，我们已经证明，促炎细胞因子肿瘤坏死因子（TNF）在终末期心力衰竭表型的发展中起着重要的作用。在动物模型中输注TNF或TNF过表达可诱导心脏扩张、心肌收缩力减弱、纤维化和细胞外基质重塑：这些变化可通过TNF可溶性受体（sTNFR）治疗逆转。事实上，全身给予sTNFR已证明对有症状的心力衰竭患者有益。由于TNF在LVAD支持的心脏中以高水平表达，我们假设用sTNFR治疗将显著改善患者恢复和LVAD撤机的能力。不幸的是，TNFR的全身给药在LVAD支持的心脏中是有问题的，因为这些患者中固有的感染风险和TNF在免疫应答中的重要作用。因此，我们假设用驱动sTNFR表达的腺相关病毒（AAV）直接注射心肌将具有saltamine效应。在我们自己的实验室中的研究已经证明，AAV载体：1）是非免疫原性的; 2）在肌肉中提供持续表达;和3）可以用心脏特异性和四环素响应性启动子构建。因此，本申请将测试以下假设：在LVAD植入时直接心肌内注射AAV-sTNFR可以在心脏中实现适应性变化，这可以促进使衰竭心脏脱离LVAD支持的能力。