Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy.
Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy.
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DOI：
10.1161/circulationaha.108.783852
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发表时间：
2009-03-10
期刊：
影响因子：
37.8
通讯作者：
Poller WC
中科院分区：
文献类型：
--
作者：
Suckau L;Fechner H;Chemaly E;Krohn S;Hadri L;Kockskämper J;Westermann D;Bisping E;Ly H;Wang X;Kawase Y;Chen J;Liang L;Sipo I;Vetter R;Weger S;Kurreck J;Erdmann V;Tschope C;Pieske B;Lebeche D;Schultheiss HP;Hajjar RJ;Poller WC
RNA干扰（RNAi）有可能成为一种新的治疗策略，在不同的医学领域。我们报告了靶向RNAi用于治疗心力衰竭（HF），这是一种由多种病因引起的人类重要疾病。通过靶向受磷蛋白（PLB）（心脏Ca 2+稳态的关键调节剂）的RNAi，在经主动脉带的大鼠模型中证明了HF的成功治疗。基因治疗依赖于重组蛋白表达作为其基本原理，而RNAi治疗利用调节RNA来实现其效果。我们描述了从腺病毒（AdV）和腺相关病毒（AAV 9）载体获得高RNAi活性的结构要求，并表明AdV短发夹RNA载体（AdV-shRNA）沉默心肌细胞（NRCM）中的PLB，并改善HF大鼠主动脉根部注射后1个月的血流动力学。为了简化长期治疗，我们开发了二聚体的亲心AAV载体（rAAV 9-shPLB），其通过静脉内注射将RNAi活性递送至心脏。心脏PLB蛋白降低至25%，HF组中的SERCA 2a抑制被挽救。与传统载体相比，rAAV 9显示出对心肌的高亲和力，但对肝脏和其他器官的低亲和力。rAAV 9-shPLB治疗将舒张（LVEDP、dp/dtmin、Tau）和收缩（缩短分数）功能参数恢复至正常范围。心肌肥厚、心肌细胞直径和心肌纤维化明显减轻。重要的是，在这些RNAi治疗期间没有证据表明microRNA失调或肝毒性。我们的数据首次显示了RNAi治疗策略在心脏病中的高疗效。
RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. We report on targeted RNAi for the treatment of heart failure (HF), an important disorder in humans resulting from multiple etiologies. Successful treatment of HF is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban (PLB), a key regulator of cardiac Ca2+ homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy employs regulatory RNAs to achieve its effect. We describe structural requirements to obtain high RNAi activity from adenoviral (AdV) and adeno-associated virus (AAV9) vectors and show that an AdV short hairpin RNA vector (AdV-shRNA) silenced PLB in cardiomyocytes (NRCMs) and improved hemodynamics in HF rats 1 month after aortic root injection. For simplified long-term therapy we developed a dimeric cardiotropic AAV vector (rAAV9-shPLB) delivering RNAi activity to the heart via intravenous injection. Cardiac PLB protein was reduced to 25% and SERCA2a suppression in the HF groups was rescued. In contrast to traditional vectors rAAV9 shows high affinity for myocardium, but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (LVEDP, dp/dtmin, Tau) and systolic (fractional shortening) functional parameters to normal range. The massive cardiac dilation was normalized and the cardiac hypertrophy, cardiomyocyte diameter and cardiac fibrosis significantly reduced. Importantly, there was no evidence of microRNA deregulation or hepatotoxicity during these RNAi therapies. Our data show, for the first time, high efficacy of an RNAi therapeutic strategy in a cardiac disease.