Zouein Fouad A, Booz George W
Department of Pharmacology and Toxicology, School of Medicine and The Jackson Center for Heart Research Jackson, Mississippi USA ; The Cardiovascular-Renal Research Center, The University of Mississippi Medical Center Jackson, Mississippi USA.
F1000Prime Rep. 2013 Aug 1;5:27. doi: 10.12703/P5-27. eCollection 2013.
Heart failure is a progressive, debilitating disease that is characterized by inadequate contractility of the heart. With an aging population, the incidence and economic burden of managing heart failure are anticipated to increase substantially. Drugs for heart failure only slow its progression and offer no cure. However, results of recent clinical trials using recombinant adeno-associated virus (AAV) gene delivery offer the promise, for the first time, that heart failure can be reversed. The strategy is to improve contractility of cardiac muscle cells by enhancing their ability to store calcium through increased expression of the sarco(endo)plasmic reticulum Ca(2+)-ATPase pump (SERCA2a). Preclinical trials have also identified other proteins involved in calcium cycling in cardiac muscle that are promising targets for gene therapy in heart failure, including the following: protein phosphatase 1, adenylyl cyclase 6, G-protein-coupled receptor kinase 2, phospholamban, SUMO1, and S100A1. These preclinical and clinical trials represent a "quiet revolution" that may end up being one of the most significant and remarkable breakthroughs in modern medical practice. Of course, a number of uncertainties remain, including the long-term utility and wisdom of improving the contractile performance of "sick" muscle cells. In this regard, gene therapy may turn out to be a way of buying additional time for actual cardiac regeneration to occur using cardiac stem cells or induced pluripotent stem cells.
心力衰竭是一种进行性、使人衰弱的疾病，其特征是心脏收缩力不足。随着人口老龄化，预计心力衰竭的发病率和管理其的经济负担将大幅增加。治疗心力衰竭的药物只能减缓其进展，无法治愈。然而，最近使用重组腺相关病毒（AAV）基因递送的临床试验结果首次带来了心力衰竭可以逆转的希望。该策略是通过增加肌浆网Ca(2+)-ATP酶泵（SERCA2a）的表达来增强心肌细胞储存钙的能力，从而改善心肌细胞的收缩力。临床前试验还确定了其他参与心肌钙循环的蛋白质，它们是心力衰竭基因治疗的有前景的靶点，包括以下这些：蛋白磷酸酶1、腺苷酸环化酶6、G蛋白偶联受体激酶2、受磷蛋白、SUMO1和S100A1。这些临床前和临床试验代表了一场“悄然的革命”，最终可能成为现代医学实践中最重要、最显著的突破之一。当然，仍存在一些不确定性，包括改善“患病”肌肉细胞收缩性能的长期效用和合理性。在这方面，基因治疗可能会成为一种利用心脏干细胞或诱导多能干细胞实现实际心脏再生的额外时间的方法。
