AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy
AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy
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DOI：
10.1016/j.yjmcc.2012.05.002
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发表时间：
2012-08-01
影响因子：
5
通讯作者：
Duan, Dongsheng
中科院分区：
文献类型：
--
作者：
Bostick, Brian;Shin, Jin-Hong;Duan, Dongsheng
杜氏肌营养不良症（DMD）是一种致命的遗传性疾病所造成的缺乏肌膜蛋白dystrophin。扩张型心肌病导致心力衰竭是DMD发病率和死亡率的重要来源。我们最近证明了使用腺相关病毒（AAV）介导的微肌营养不良蛋白基因治疗在16至20岁的肌营养不良蛋白缺失mdx小鼠中改善DMD心脏病。DMD患者在预期寿命接近尾声时会出现严重的心脏病。同样，mdx小鼠在超过21个月大时，心脏病表现出严重恶化。为了更严格地测试微肌营养不良蛋白疗法，我们治疗了21.2至22.7 m龄的mdx小鼠（平均22.1 +/- 0.2个月：N = 8）。将Delta R4-23/Delta C微小肌养蛋白基因包装在亲心性AAV-9病毒中。通过尾静脉将5 × 1012个病毒基因组颗粒/小鼠递送至mdx小鼠。基因治疗后1.7 +/- 0.2个月检查AAV转导、心肌纤维化和心脏功能。在治疗小鼠的心肌中观察到有效的微肌营养不良蛋白表达。尽管抗肌萎缩蛋白表达强烈，但心肌纤维化并未减轻。大多数血流动力学参数也没有改善。然而. ECG异常部分纠正。重要的是，治疗小鼠对多巴酚丁胺诱导的心脏死亡更具抵抗力。总之，我们首次揭示了AAV微肌养蛋白治疗终末期Duchenne扩张型心肌病的潜在益处和局限性。我们的研究结果对AAV基因治疗扩张型心肌病和心力衰竭具有重要意义。(C)2012爱思唯尔有限公司保留所有权利。
Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of the sarcolemmal protein dystrophin. Dilated cardiomyopathy leading to heart failure is a significant source of morbidity and mortality in DMD. We recently demonstrated amelioration of DMD heart disease in 16 to 20-rn-old dystrophin-null mdx mice using adeno-associated virus (AAV) mediated micro-dystrophin gene therapy. DMD patients show severe heart disease near the end of their life expectancy. Similarly, mdx mice exhibit profoundly worsening heart disease when they reach beyond 21 months of age. To more rigorously test micro-dystrophin therapy, we treated mdx mice that were between 21.2 and 22.7-m-old (average, 22.1 +/- 0.2 months: N = 8). The Delta R4-23/Delta C micro-dystrophin gene was packaged in the cardiotropic AAV-9 virus. 5 x 10(12) viral genome particles/mouse were delivered to mdx mice via the tail vein. AAV transduction, myocardial fibrosis and heart function were examined 1.7 +/- 0.2 months after gene therapy. Efficient micro-dystrophin expression was observed in the myocardium of treated mice. Despite the robust dystrophin expression, myocardial fibrosis was not mitigated. Most hemodynamic parameters were not improved either. However. ECG abnormalities were partially corrected. Importantly, treated mice became more resistant to dobutamine-induced cardiac death. In summary, we have revealed for the first time the potential benefits and limitations of AAV micro-dystrophin therapy in end-stage Duchenne dilated cardiomyopathy. Our findings have important implications for the use of AAV gene therapy in dilated cardiomyopathy and heart failure. (C) 2012 Elsevier Ltd. All rights reserved.