Yue Yongping, Skimming Jeffrey W, Liu Mingju, Strawn Tammy, Duan Dongsheng
Department of Molecular Microbiology and Immunology, The University of Missouri, School of Medicine, Columbia 65212, USA.
Hum Mol Genet. 2004 Aug 1;13(15):1669-75. doi: 10.1093/hmg/ddh174. Epub 2004 Jun 9.
Gene therapy holds great promise for curing Duchenne muscular dystrophy (DMD), the most common fatal inherited childhood muscle disease. Success of DMD gene therapy depends upon functional improvement in both skeletal and cardiac muscle. Numerous gene transfer studies have been performed to correct skeletal muscle pathology, yet little is known about cardiomyopathy gene therapy. Since complete transduction of the entire heart is an impractical goal, it becomes critical to determine the minimal level of correction needed for successful DMD cardiomyopathy gene therapy. To address this question, we generated heterozygous mice that persistently expressed the full-length dystrophin gene in 50% of the cardiomyocytes of mdx mice, a model for DMD. We questioned whether dystrophin expression in half of the heart cells was sufficient to prevent stress-induced cardiomyopathy. Heart function of mdx mouse is normal in the absence of external stress. To determine the therapeutic effect, we challenged 3-month-old mice with beta-isoproterenol. Cardiomyocyte sarcolemma integrity was significantly impaired in mdx but not in heterozygous and C57Bl/10 mice. Importantly, in vivo closed-chest hemodynamic assays revealed normal left ventricular function in beta-isoproterenol-stimulated heterozygous mice. Since the expression profile in the heterozygous mice mimicked viral transduction, we conclude that gene therapy correction in 50% of the heart cells may be sufficient to treat cardiomyopathy in mdx mice. This finding may also apply to the gene therapy of other inherited cardiomyopathies.
基因治疗在治愈杜氏肌营养不良症（DMD）方面具有巨大潜力，DMD是最常见的致命性遗传性儿童肌肉疾病。DMD基因治疗的成功取决于骨骼肌和心肌功能的改善。已经进行了大量基因转移研究来纠正骨骼肌病理，但对心肌病基因治疗知之甚少。由于完全转导整个心脏是一个不切实际的目标，因此确定成功的DMD心肌病基因治疗所需的最低纠正水平变得至关重要。为了解决这个问题，我们构建了杂合小鼠，其在mdx小鼠（一种DMD模型）50%的心肌细胞中持续表达全长抗肌萎缩蛋白基因。我们质疑心脏细胞中一半表达抗肌萎缩蛋白是否足以预防应激诱导的心肌病。在没有外部应激的情况下，mdx小鼠的心脏功能正常。为了确定治疗效果，我们用β-异丙肾上腺素对3个月大的小鼠进行刺激。mdx小鼠的心肌细胞膜完整性显著受损，但杂合小鼠和C57Bl/10小鼠未受损。重要的是，体内闭胸血流动力学分析显示，在β-异丙肾上腺素刺激的杂合小鼠中左心室功能正常。由于杂合小鼠的表达谱模拟了病毒转导，我们得出结论，50%的心脏细胞中的基因治疗纠正可能足以治疗mdx小鼠的心肌病。这一发现也可能适用于其他遗传性心肌病的基因治疗。
