Improved Methods for Myocardial Gene Transfer

描述(申请人提供)：心律失常，终末期冠状动脉疾病，以及特发性或遗传性心肌病都是心脏疾病的例子，没有足够的治疗选择。基因疗法最初被吹捧为治疗所有这些疾病以及许多其他疾病的潜在疗法。不幸的是，基因治疗最初的承诺从未完全实现。在开发这种新的治疗方法时遇到的一些困难包括转基因传递不充分，对载体和/或转基因的免疫反应，以及在传递后无法维持基因表达。这项提议的重点是转基因输送问题，目的是开发新的方法，将转基因高效、安全和有效地输送到目标区域的所有细胞。这一提议的中心假设是，对与交付相关的变量进行系统的探索，无论是全球的还是局部的，将允许开发成功的基因转移的新工具。为了探索这一假设，我们将致力于三个目标：1)通过系统地评估血流动力学和物理变量对递送效率的作用，实现安全、均匀、全局的心脏基因转移；2)通过开发针对注射的解剖和电生理靶向的方法，提高局部心肌基因转移的精确度；以及3)通过操纵基因转移载体来提高心肌基因转移的安全性和效率。这些目标的成功实现将使基因治疗更接近于实现其作为心血管治疗的潜力。

DESCRIPTION (provided by applicant): Arrhythmias, end-stage coronary disease, and idiopathic or inherited cardiomyopathies are all examples of cardiac diseases with inadequate therapeutic options. Gene therapy was initially touted as the potential cure for all of these along with many other diseases. Unfortunately, the initial promise of gene therapy has never been fully realized. Some of the difficulties encountered while developing this new therapeutic include inadequate delivery of the transgene, immune reaction to the vector and/or the transgene, and an inability to sustain gene expression after delivery. This proposal focuses on the problem of transgene delivery, with a goal of developing new methods for efficient, safe and effective delivery of the transgene to all of the cells in the target region. The central hypothesis of this proposal is that a systematic exploration of the variables relevant to delivery, either global or local, will allow development of new tools for successful gene transfer. To explore this hypothesis, we will address three aims: 1) To achieve safe, homogeneous, global gene transfer to the heart by systematically evaluating the role of hemodynamic and physical variables on the efficiency of delivery; 2) To improve the precision of focal myocardial gene transfer by developing methods for anatomical and electrophysiological targeting of the injection; and 3) To improve the safety and efficiency of myocardial gene transfer by manipulation of the gene transfer vector. Successful completion of these aims will bring gene therapy one-step closer to realizing its potential as a cardiovascular therapeutic.