Improved Methods for Myocardial Gene Transfer

描述（由申请人提供）：心律失常、终末期冠状动脉疾病和特发性或遗传性心肌病都是治疗选择不足的心脏疾病的例子。 基因疗法最初被吹捧为所有这些沿着许多其他疾病的潜在治愈方法。 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的递送不足、对载体和/或转基因的免疫反应以及递送后不能维持基因表达。 该提案集中于转基因递送的问题，目标是开发用于将转基因高效、安全和有效地递送至靶区域中的所有细胞的新方法。 这一建议的核心假设是，系统地探索与全球或局部交付相关的变量，将允许开发成功的基因转移的新工具。 为了探索这一假说，我们将提出三个目标：1）通过系统地评估血液动力学和物理变量对递送效率的作用，实现安全、均匀、全局的基因转移到心脏; 2）通过开发注射的解剖和电生理靶向方法，提高局灶性心肌基因转移的精确性; 3）通过基因转移载体的操作，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.