Translational studies in Heart Failure Gene Therapy

心力衰竭基因治疗的转化研究

基本信息

批准号：
7681880
负责人：
Charles R Bridges
金额：
$ 3.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681880
关键词：
Achievement Adrenergic Agents Adult American Animal Model Animals Anterior Descending Coronary Artery Biochemical Biochemical Markers Blood Circulation Canis familiaris Cannulations Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiomyopathies Cardiopulmonary Bypass Catheters Coronary Circulation Coupled Data Devices Dilated Cardiomyopathy Emerging Technologies Gene Delivery Gene Expression Heart Heart Transplantation Heart failure Human In Situ Invasive LacZ Genes Lead Left Life Ligation Magnetic Resonance Imaging Mechanics Mediating Methodology Methods Modeling Mus Muscle Cells Myocardial Operative Surgical Procedures Oryctolagus cuniculus Phenotype Phosphotransferases Probability Procedures Rate Recombinant adeno-associated virus (rAAV)Recombinants Relative (related person)Rodent Model Serotyping Sheep Signal Transduction Staging Techniques Technology Testing Therapeutic Effect Time Transgenic Mice Work adrenergic clinically relevant cost gene therapy hemodynamics improved in vivo indexing marker transgenes novel novel strategies promoter receptor success therapeutic transgene transduction efficiency translational study vector ventricular assist device

项目摘要

DESCRIPTION (provided by applicant): This year, one million Americans will die of heart failure at a cost of 25 billion dollars. Yet, only two thousand Americans will receive heart transplants and even fewer will receive mechanical ventricular assist devices. Gene therapy is an important emerging technology with the potential to save thousands of lives. Correction of the heart failure phenotype has been convincingly demonstrated in transgenic mice, rabbit and rodent models of heart failure using the beta adreno-receptor kinase C-terminus (BARKct)) as a therapeutic transgene. Prior to our work, none of the delivery techniques utilized to date has been clinically translatable and had high global myocyte transduction efficiency. These observations galvanize our central hypothesis: the rate-limiter in the quest for clinically relevant heart failure gene therapy is the successful achievement of global vector-mediated gene delivery to a significant percentage of cardiac myocytes in situ in a translational animal model. Here we present our success in developing an exciting new cardiac surgical technique that efficiently delivers marker transgenes to adult large animal cardiac myocytes in situ using cardiopulmonary bypass with surgical isolation of the heart in vivo and in situ, coupled with multiple-pass recirculation of recombinant vector in the coronary circulation. This procedure allows for control of multiple variables to optimize myocyte gene delivery efficiency while minimizing the probability of collateral gene expression. We also present exciting new data using both constitutive and cardiac-specific promoters demonstrating highly efficient cardiac myocyte transduction with AAV6 in a heart failure model and preliminary data with AAV9 in the murine heart. In the first year we further optimize the global delivery technique using these novel AAV serotypes in the normal sheep heart. In years two through four we use the improved gene delivery methodology to administer novel AAV constructs encoding BARKct to the heart in an ovine model that closely mimics human ischemic cardiomyopathy. We use 3D MRI and invasive hemodynamic studies to assess load-independent and load-dependent indices of cardiac mechanics and myocardial energetics. The effects of gene expression on remodeling, adrenergic cycling, heart failure markers and survival will be assessed for up to one year. Successful completion of this study may lead to alternatives to heart transplantation and permanent mechanical assist devices in the treatment of end stage heart failure.

描述（由申请人提供）：今年，一百万美国人将因心力衰竭而死，耗资250亿美元。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。基因疗法是一项重要的新兴技术，有可能挽救数千种生命。在转基因小鼠，兔子和啮齿动物模型中，使用β腺癌激酶C-末端（BARKCT）作为治疗转基因的转基因小鼠，兔子和啮齿动物模型，对心力衰竭表型的校正已令人信服。在我们的工作之前，迄今为止使用的输送技术在临床上都无法翻译，并且具有较高的全球心肌转导效率。这些观察结果激发了我们的中心假设：寻求临床相关心力衰竭基因治疗的率限制者是全球载体介导的基因递送的成功实现，以在翻译动物模型中原位的大量心肌细胞。在这里，我们在开发一种令人兴奋的新心脏外科技术方面取得了成功，该技术可以有效地将标志物转trans基因转trans基因转移到成年的大型动物心脏心肌细胞，并使用心肺旁路，并在体内和原位将心脏的手术分离，并与冠状动脉循环中重组载体的多通过循环相连。该过程允许控制多个变量，以优化肌细胞基因的递送效率，同时最大程度地减少附带基因表达的可能性。我们还使用本构和心脏特异性启动子介绍了令人兴奋的新数据，这些启动子在心力衰竭模型中使用AAV6表现出高效的心肌细胞转导，并在鼠心脏中使用AAV9进行初步数据。在第一年，我们使用这些新型AAV血清型在正常绵羊心脏中进一步优化了全球交付技术。在第二至四年级中，我们使用改进的基因递送方法来管理新型的AAV构造，将编码BARKCT的卵巢模型与人类缺血性心肌病密切相关。我们使用3D MRI和侵入性血液动力学研究来评估心脏力学和心肌能量的非负荷依赖性和载荷依赖性指标。基因表达对重塑，肾上腺素能循环，心力衰竭标记和存活率的影响将被评估长达一年。这项研究的成功完成可能会导致心脏移植和永久性机械辅助设备的替代方案，以治疗末期心力衰竭。