Translational Studies in Heart Failure Gene Therapy

心力衰竭基因治疗的转化研究

• 批准号: 9193269
• 负责人: Charles R Bridges
• 金额: $ 66.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193269
• 关键词: Translational; Studies; Heart; Failure; Gene

DESCRIPTION (provided by applicant): There are 22 million people worldwide with heart failure with a total cost this in the U.S. this year of 37 billion dollars. Yet, only two thousand Americans will receive heart transplants and even fewer will receive mechanical ventricular assist devices. Recently, it has been demonstrated that AAV9 encoding S100A1 reverses remodeling in a porcine model of ischemic heart failure with near complete molecular and functional rescue of the heart failure phenotype, the first-ever dramatic success of gene therapy for heart failure in a large animal model. Simultaneously, our collaborator, Dr. Roger Hajjar's pioneering work lead to the first-ever successful Phase IIA clinical trial of heart failure gene therapy (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease), the CUPID trial, using AAV1 encoding SERCA2a as therapy for patients with advanced heart failure. However, both the SERCA2a (CUPID) clinical trial, and the preclinical studies using the S100A1 transgene, utilized inefficient (intracoronary delivery, CUPID trial), and regional rather than global vector delivery methods (pressurized coronary venous retroinfusion, S100A1 preclinical study), severely limiting their respective potential therapeutic impact in patients. In our prior funding period, we developed a novel vector- mediated cardiac gene delivery platform, "Molecular Cardiac Surgery with Recirculating Delivery" (MCARD) a safe, exciting new potentially minimally invasive cardiac surgical technique that uniquely allows for in situ, multiple-pass recirculation of recombinant vector in the isolated coronary circulation in large animals. MCARD leads to a >100 fold increase in the number of vector genomes delivered to the LV compared to existing gene delivery methods and is 10000 times more geographically specific to the heart. We plan to utilize MCARD, the most efficient and cardiac-specific gene delivery platform in the world to deliver the highly cardiotropic AAV serotypes scAAV6, scAAV9 and ssAAV9) encoding the two most promising transgenes (S100A1 and SERCA2a) in ovine ischemic heart failure models that closely mimic human ischemic cardiomyopathy. We use 3D MRI studies to assess load-independent and load- dependent indices of cardiac mechanics and myocardial energetics. The effects of gene expression on remodeling, calcium signaling, molecular heart failure markers and survival will be assessed for up to one year. This proposal will lead directly to promising new clinical trials for heart failure.

描述（由申请人提供）：全球有2200万人心力衰竭，今年在美国的总费用为370亿美元。然而，只有两千名美国人会接受心脏移植，甚至更少会收到机械的心室辅助设备。最近，已经证明编码S100A1的AAV9在缺血性心力衰竭的猪模型中逆转重塑，并几乎完整的分子和功能拯救心力衰竭表型，这是基因疗法在大型动物模型中为心力衰竭的第一个巨大成功。同时，我们的合作者Roger Hajjar博士的开拓性工作导致了心力衰竭基因疗法的第一阶段IIA临床试验（心脏病中的基因治疗钙上调），CUPID试验，使用AAV1编码SERCA2A治疗，用于治疗患有SERCA2A的治疗。但是，使用S100A1转基因的SERCA2A（CUPID）临床试验和临床前研究都使用效率低下（冠状动脉内输送，丘比特试验）以及区域而不是全球载体递送方法（加压冠状冠状静脉输送方法，S100A1预先研究），S100A1预固化性研究），严重限制了他们的潜在患者。在以前的资金期间，我们开发了一种新型的矢量介导的心脏基因输送平台，“带有循环递送的分子心脏手术”（MCARD）一种安全，令人兴奋的新的潜在的潜在微创心脏外科手术技术，可以独特地允许在大型动物中隔离的隔离式循环中重组载体的本地重组。与现有的基因输送方法相比，McArd导致载入LV的矢量基因组数量增加> 100倍，并且对心脏的地理特异性特异性增加了10000倍。我们计划利用McArd，这是世界上最有效，最特定的基因输送平台，以在卵巢性部失败模型模型中提供两个最有前途的转基因（S100A1和SERCA2A），以编码两个最有前途的转基因（S100A1和SERCA2A），这些模型在冰川症状过失的MIMIC MIMIC MANETATHICOPOPOPIOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPOPO.我们使用3D MRI研究来评估心脏力学和心肌能量学的非负荷依赖性和载荷依赖性指数。基因表达对重塑，钙信号，分子心力衰竭标记和存活率的影响将长达一年。该提案将直接导致有望进行心力衰竭的新临床试验。