Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, USA.
Can J Cardiol. 2011 May-Jun;27(3):265-83. doi: 10.1016/j.cjca.2011.02.005.
Chronic heart failure is one of the leading causes of morbidity and mortality in Western countries and is a major financial burden to the health care system. Pharmacologic treatment and implanting devices are the predominant therapeutic approaches. They improve survival and have offered significant improvement in patient quality of life, but they fall short of producing an authentic remedy. Cardiac gene therapy, the introduction of genetic material to the heart, offers great promise in filling this void. In-depth knowledge of the underlying mechanisms of heart failure is, obviously, a prerequisite to achieve this aim. Extensive research in the past decades, supported by numerous methodological breakthroughs, such as transgenic animal model development, has led to a better understanding of the cardiovascular diseases and, inadvertently, to the identification of several candidate genes. Of the genes that can be targeted for gene transfer, calcium cycling proteins are prominent, as abnormalities in calcium handling are key determinants of heart failure. A major impediment, however, has been the development of a safe, yet efficient, delivery system. Nonviral vectors have been used extensively in clinical trials, but they fail to produce significant gene expression. Viral vectors, especially adenoviral, on the other hand, can produce high levels of expression, at the expense of safety. Adeno-associated viral vectors have emerged in recent years as promising myocardial gene delivery vehicles. They can sustain gene expression at a therapeutic level and maintain it over extended periods of time, even for years, and, most important, without a safety risk.
慢性心力衰竭是西方国家发病率和死亡率的主要原因之一，也是医疗保健系统的主要经济负担。药物治疗和植入设备是主要的治疗方法。它们提高了生存率，并显著改善了患者的生活质量，但仍未能提供真正的治疗方法。心脏基因治疗，即将遗传物质引入心脏，为填补这一空白提供了巨大的希望。深入了解心力衰竭的潜在机制显然是实现这一目标的前提。在过去几十年中，大量方法学突破的支持下，如转基因动物模型的开发，使人们对心血管疾病有了更好的理解，并无意中确定了几个候选基因。在可用于基因转移的基因中，钙循环蛋白尤为突出，因为钙处理异常是心力衰竭的关键决定因素。然而，一个主要的障碍是开发一种安全但有效的输送系统。非病毒载体已广泛应用于临床试验，但它们不能产生显著的基因表达。另一方面，病毒载体，特别是腺病毒，可以产生高水平的表达，但代价是安全性。近年来，腺相关病毒载体已成为有前途的心肌基因传递载体。它们可以在治疗水平上维持基因表达，并在延长的时间内维持表达，甚至长达数年，而且最重要的是没有安全风险。
