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.

在美国收缩功能障碍继发的心力衰竭是美国流行比例的疾病，尽管药物疗法可以延长生存率，减少住院治疗并减轻症状，但这种疾病是渐进的，许多患者最终出现了暴发和/或无情症状。在这组患者中，左心室辅助装置（LVAD）已用于在LVAD植入和心脏移植之间“桥接”患者。有趣的是，在一部分患者中，LVAD可以随着时间的流逝而断奶，导致研究人员假设LVAD支持可能使患者成为“恢复桥梁”，研究表明，研究表明，慢性LVAD支持后，肌细胞功能有益于变化。然而，LVAD支持的心脏还表明纤维化，细胞凋亡和细胞外基质重塑增加。这些报告导致我们推测，针对抑制基质重塑的治疗干预措施可能会提高使患者从LVAD支持中解脱的能力。在过去的五年中，我们证明了促炎性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重要作用。 TNF的输注或TNF在动物模型中的过表达可引起心脏稀释，心脏收缩率降低，纤维化和细胞外基质重塑：可以用TNF可溶性受体（STNFR）处理可以反转的变化。实际上，STNFR的系统给药表现出对有症状性心力衰竭患者的益处。由于TNF在LVAD支持的心脏中以高水平表达，因此我们假设用STNFR治疗将显着提高患者恢复和LVAD断奶的能力。不幸的是，由于这些患者的固有感染风险以及TNF在免疫反应中的重要作用，因此在LVAD支持心脏中，全身给药是有问题的。因此，我们假设用腺相关病毒直接注射心肌（AAV）驱动STNFR表达将产生有益的作用。在我们自己的实验室中的研究表明，AAV载体：1）是非免疫原性的； 2）在肌肉中提供持续的表达； 3）可以用心脏特异性和四环素反应启动子来构建。因此，该应用将检验以下假设：LVAD植入时直接心膜内注射AAV-STNFR可能会影响心脏的适应性变化，从而有助于促进LVAD支持的心脏失败的能力。