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.

在美国，由收缩功能障碍引起的心力衰竭是一种流行疾病，有500多万人受到影响。心力衰竭每年导致100多万人住院，400,000人死亡，400亿美元的医疗费用，而严重心力衰竭患者的5年生存率不到50%。药物和设备治疗的最新进展在一定程度上改善了症状，减少了住院时间，延长了生存时间。然而，心力衰竭是一种进行性疾病，许多患者最终会出现坚持不懈的终末期症状。移植为这些患者提供了唯一明确的治疗方法，但捐赠者供应的数量很少，限制了这种治疗仅限于少数患者。最近，机械左心室辅助装置(LVAD)的发展提供了 一座通向移植的新“桥梁”。LVAD的使用越来越多，也为测试基因转移等新疗法是否安全和潜在有效提供了机会。 肌浆网钙ATPase 2a(SERCA2a)将钙装入肌浆 网状细胞(SR)，在心力衰竭时被下调。在腺病毒和腺相关病毒(AAV)基因转移的动物模型中，使用腺病毒或腺相关病毒载体恢复SERCA2a水平已被证明可以改善动物模型的功能、代谢和/或存活。在第一个资助期，我们已经开始测试在心力衰竭患者放置LVAD时直接注射表达SERCA2a的AAV(AAV6-CMV-SERCA2a)是否安全，是否可以恢复SERCA2a的正常表达。我们将在下一个资助期延长我们先前的研究。我们将：1)比较直接注射和冠状动脉内注射 该研究的目的是：1)在缺血性和非缺血性心肌病的动物模型中采用灌注法和无处不在的心脏特异性启动子作为基因输送方法；2)进行一期临床试验，测试在植入左冠状动脉旁路移植术时两种不同的全球输送AAV6-SERCA2a方法的安全性和潜在疗效；3)进行1/2期临床试验，测试这种疗法在接受其他心脏外科手术的心力衰竭患者中的安全性和潜在有效性；以及4)开始临床前测试可能改善心脏钙循环的其他基因。这些研究将确定使用SERCA2a作为治疗晚期心力衰竭患者的基因转移的潜力。