Gene Therapy During LVAD Support

LVAD 支持期间的基因治疗

• 批准号: 7139374
• 负责人: Barry London
• 金额: $ 62.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139374
• 关键词: adeno associated virus group; biotechnology; calcium transporting ATPase; cardiovascular disorder; cardiovascular surgery; circulatory assist; clinical trial phase I; cooperative study; dogs; gene delivery system; gene therapy; heart failure; human subject; human therapy evaluation; injection /infusion; myocardium disorder; patient oriented research; perfusion; sarcoplasmic reticulum; swine

Heart failure due to systolic dysfunction is a disease of epidemic proportions in the U.S. with over 5 million effected individuals. Heart failure accounts for over one million hospitalizations, 400,000 deaths, and 40 billion dollars in health care expenses each year with a 5-year survival of less than 50% in severely affected individuals. Recent advances in pharmacological and device therapy have improved symptoms, decreased hospitalizations and lengthened survival to some extent. Heart failure is a progressive disease, however, and many patients eventually develop unremitting end-stage symptoms. Transplantation provides the only definitive treatment for these patients, but the small donor supply limits this therapy to only a few patients. More recently, the development of mechanical left ventricular assist devices (LVADs) has provided a novel "bridge" to transplantation. The increasing use of LVADs also provides the opportunity to test whether novel therapies such as gene transfer are safe and potentially efficacious. The sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) loads calcium into the sarcoplasmic reticulum (SR) and is downregulated in heart failure. Restoring SERCA2a levels using adenoviral or adeno-associated viral vectors has been shown to improve function, metabolism and/or survival in animal models using adenoviral and adeno-associated viral (AAV) gene transfer. During the first funding period, we have begun to test whether direct injection of an AAV expressing SERCA2a (AAV6-CMV-SERCA2a) at the time of LVAD placement in heart failure patients is safe and can restore SERCA2a expression to normal. We will extend our prior studies during the next funding period. We will: 1) compare direct injection vs. intracoronary perfusion and ubiquitous vs. cardiac specific promoters as the method of gene delivery in animal models of ischemic and non-ischemic cardiomyopathies; 2) perform a Phase 1 clinical trial testing the safety and potential efficacy of two different methods of global delivery of AAV6-SERCA2a at the time of LVAD placement; 3) perform a Phase 1/2 clinical trial to test the safety and potential efficacy of this treatment in heart failure patients having other cardiac surgical procedures; and 4) begin preclinical testing of other genes that may improve calcium cycling in the heart. These studies will determine the potential of gene transfer using SERCA2a as a treatment for patients with advanced heart failure.

由于收缩功能障碍引起的心力衰竭是美国的流行比例疾病，受影响超过500万。心力衰竭占每年超过100万个住院，40万人死亡和400亿美元的医疗保健费用，受影响的人的5年生存率不到50％。药理学和设备治疗的最新进展改善了症状，住院下降并在某种程度上延长了生存率。心力衰竭是一种进行性疾病，但是许多患者最终会出现不懈的终点症状。移植为这些患者提供了唯一的明确治疗方法，但是小供体供应将这种疗法限制在只有少数患者中。最近，机械左心室辅助设备（LVADS）的开发提供了 一个小说的“桥”移植。 LVAD的越来越多的使用还提供了测试基因转移等新型疗法是否安全且可能有效的机会。 肌质网钙ATPase 2a（SERCA2A）将钙负载到肌质中 网状（SR），心力衰竭下调。使用腺病毒或腺相关病毒载体恢复SERCA2A水平已显示可改善动物模型中使用腺病毒和腺相关病毒（AAV）基因转移的功能，代谢和/或存活。在第一个资金期间，我们已经开始测试在心力衰竭患者中LVAD放置时直接注射AAV表达SERCA2A（AAV6-CMV-SERCA2A）是否安全，并且可以使SERCA2A表达恢复正常。我们将在下一个资金期间扩展先前的研究。我们将：1）比较直接注射与冠状动脉 在缺血性和非缺血性心肌病动物模型中，灌注和无处不在的心脏促进剂与心脏特异性启动子作为基因递送的方法； 2）执行1阶段临床试验，以测试LVAD放置时两种不同方法的AAV6-SERCA2A的安全性和潜在疗效； 3）执行1/2期临床试验，以测试该治疗的安全性和潜在疗效，对具有其他心脏手术手术的心力衰竭患者； 4）开始对可能改善心脏钙循环的其他基因进行临床前测试。这些研究将确定使用SERCA2A作为晚期心力衰竭患者的基因转移的潜力。