1 Department of Molecular Microbiology and Immunology, The University of Missouri , Columbia, Missouri.
2 Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health , London, United Kingdom .
Hum Gene Ther. 2018 Jul;29(7):737-748. doi: 10.1089/hum.2017.144. Epub 2018 Mar 22.
Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6-8 kb mini-dystrophin gene in the heart holds promise to change the disease course dramatically. However, the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. Cardiac protection of the ΔH2-R19 minigene was previously studied using the cardiac-specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy. This study evaluated the ΔH2-R15 minigene using the same transgenic approach in mdx mice that had more severe cardiomyopathy. In contrast to the ΔH2-R19 minigene, the ΔH2-R15 minigene carries dystrophin spectrin-like repeats 16 to 19 (R16-19), a region that has been suggested to protect the heart in clinical studies. Cardiac expression of the ΔH2-R15 minigene normalized all aberrant electrocardiogram changes and improved hemodynamics. Importantly, it corrected the end-diastolic volume, an important diastolic parameter not rescued by ΔH2-R19 mini-dystrophin. It is concluded that that ΔH2-R15 mini-dystrophin is a superior candidate gene for heart protection. This finding has important implications in the design of the mini/micro-dystrophin gene for Duchenne cardiomyopathy therapy.
心脏病是杜氏肌营养不良症（Duchenne/Becker muscular dystrophy）患者和携带者的主要健康威胁。在心脏中表达 6-8kb 的微小肌营养不良蛋白基因有望显著改变疾病进程。然而，由于微小基因的大小超过腺相关病毒（Adeno-associated virus，AAV）基因传递的包装能力，因此难以用 AAV 基因传递来研究微小基因。先前使用心脏特异性转基因方法研究了 ΔH2-R19 微小基因对心脏的保护作用。尽管该微小基因完全正常化了骨骼肌力量，但它仅部分纠正了具有中度心肌病的肌营养不良症 nmdx 小鼠的心电图和心脏血液动力学。本研究使用相同的转基因方法在具有更严重心肌病的 mdx 小鼠中评估了 ΔH2-R15 微小基因。与 ΔH2-R19 微小基因不同，ΔH2-R15 微小基因携带肌营养不良蛋白 spectrin-like 重复 16 至 19（R16-19），该区域在临床研究中被认为可保护心脏。ΔH2-R15 微小基因在心脏中的表达使所有异常心电图变化正常化，并改善了血液动力学。重要的是，它纠正了舒张末期容积，这是 ΔH2-R19 微小肌营养不良蛋白不能挽救的重要舒张参数。结论是，ΔH2-R15 微小肌营养不良蛋白是心脏保护的更佳候选基因。这一发现对杜氏肌营养不良症治疗中小微肌营养不良蛋白基因的设计具有重要意义。
