Cardiac arrhythmias are a major healthcare problem in the developed world. The American Heart Association 2017 statistical report indicates that atrial fibrillation, the most common cardiac rhythm disorder, has an ≈25% lifetime incidence and annual costs of ≈26 billion dollars, whereas sudden cardiac death (usually caused by malignant arrhythmias) affects fewer individuals (just under 200 000 Americans/year) but has more disastrous consequences.1 There have been a variety of improvements in arrhythmia therapy over the past decades, particularly in the realm of nonpharmacological approaches, but many challenges remain.2 Article, see p 525 One area with great promise is the induced modification of cardiac gene expression to produce the targeted downregulation or overexpression of specific gene products (gene therapy).3 The first reported experimental application of gene therapy was for the control of ventricular response rate in atrial fibrillation.4 Since then, a wide range of developments has occurred in the design of gene therapy, the development of gene delivery systems (including cardiac-selective delivery vectors, promoter-selection and product design, and production methods), and therapeutic-targeting strategy.3 Inherited arrhythmia syndromes caused by ion-channel dysfunction lend themselves naturally to gene therapy because most result from gain or loss of function of a single gene product that can be targeted specifically. In 2014, Denegri et al5 reported a fascinating proof-of-principle study demonstrating that a single injection of a cardiotropic adeno-associated virus (serotype-9, AAV9) carrying wild-type calsequestrin-2 is able to produce long-term suppression (over the full animal life span) of the arrhythmic phenotype in mice with a loss-of-function mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT). The mutation that was targeted produces a recessive form of CPVT, in which affected individuals produce no functional protein and the only curative treatment possible is to restore the full functional wild-type gene product in the heart. The wild-type …

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等位基因特异的基因沉默

心脏心律不齐是发达国家的主要医疗保健问题。美国心脏协会2017年的统计报告表明，心房纤颤是最常见的心律失常，终生发病率约为25％，每年的费用约为260亿美元，而突发性心源性死亡（通常由恶性心律失常引起）影响的个体较少（每年只有不到20万美国人），但后果更为惨重。1在过去的几十年中，心律失常的治疗有了很多改进，特别是在非药物治疗领域，但仍然存在许多挑战。2文章，请参阅第525页很有希望的领域是心脏基因表达的诱导修饰，以产生特定基因产物的靶向下调或过表达（基因治疗）。3基因治疗的第一个实验性应用报道是用于控制心房纤颤的心室反应率。4此后，基因治疗的设计，基因传递系统（包括心脏选择性）的开发取得了广泛的进展。 3）由离子通道功能障碍引起的遗传性心律失常综合症自然适用于基因治疗，因为大多数起因于单个基因功能的获得或丧失可以明确定位的产品。2014年，Denegri等[5]进行了一项引人入胜的原理验证研究，证明了单次注射与心型腺相关的病毒（9型血清型，携带野生型calsequestrin-2的AAV9）能够在具有功能丧失突变的小鼠中长期抑制（在整个动物寿命期内）心律失常表型，从而导致儿茶酚胺多态性室性心动过速（CPVT）。靶向的突变产生隐性CPVT，其中受影响的个体不产生功能蛋白，唯一可能的治疗方法是在心脏中恢复完整功能的野生型基因产物。野生型… 其中受影响的个体不产生功能性蛋白质，唯一可能的治疗方法是在心脏中恢复完整的功能性野生型基因产物。野生型… 其中受影响的个体不产生功能蛋白，唯一可能的治疗方法是在心脏中恢复完整功能的野生型基因产物。野生型…