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Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.ymthe.2019.12.011
Nalinda B Wasala 1 , Yongping Yue 1 , William Lostal 1 , Lakmini P Wasala 1 , Nandita Niranjan 2 , Roger J Hajjar 3 , Gopal J Babu 2 , Dongsheng Duan 4
Affiliation  

Loss of dystrophin leads to Duchenne muscular dystrophy (DMD). A pathogenic feature of DMD is the significant elevation of cytosolic calcium. Supraphysiological calcium triggers protein degradation, membrane damage, and eventually muscle death and dysfunction. Sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase (SERCA) is a calcium pump that transports cytosolic calcium to the SR during excitation-contraction coupling. We hypothesize that a single systemic delivery of SERCA2a with adeno-associated virus (AAV) may improve calcium recycling and provide long-lasting benefits in DMD. To test this, we injected an AAV9 human SERCA2a vector (6 × 1012 viral genome particles/mouse) intravenously to 3-month-old mdx mice, the most commonly used DMD model. Immunostaining and western blot showed robust human SERCA2a expression in the heart and skeletal muscle for 18 months. Concomitantly, SR calcium uptake was significantly improved in these tissues. SERCA2a therapy significantly enhanced grip force and treadmill performance, completely prevented myocardial fibrosis, and normalized electrocardiograms (ECGs). Cardiac catheterization showed normalization of multiple systolic and diastolic hemodynamic parameters in treated mice. Importantly, chamber dilation was completely prevented, and ejection fraction was restored to the wild-type level. Our results suggest that a single systemic AAV9 SERCA2a therapy has the potential to provide long-lasting benefits for DMD.

中文翻译:

单一SERCA2a治疗在Duchenne肌肉营养不良的小鼠模型中改善了18个月的扩张型心肌病。

肌营养不良蛋白的丧失导致杜氏肌营养不良症(DMD)。DMD的致病特征是胞质钙的显着升高。超生理学钙触发蛋白质降解,膜损伤,最终导致肌肉死亡和功能障碍。肌浆/内质网(SR)钙ATPase(SERCA)是一种钙泵,可在激发-收缩偶联过程中将胞浆钙转运到SR。我们假设,与腺相关病毒(AAV)一起单次全身递送SERCA2a可以改善钙的循环利用,并在DMD中提供长期的益处。为了对此进行测试,我们向3个月大的mdx小鼠(最常用的DMD模型)静脉内注射了AAV9人SERCA2a载体(6×1012病毒基因组颗粒/小鼠)。免疫染色和蛋白质印迹显示18个月内,人SERCA2a在心脏和骨骼肌中表达稳定。同时,在这些组织中SR钙的摄取显着改善。SERCA2a治疗显着增强了抓地力和跑步机性能,完全防止了心肌纤维化,并使心电图正常化(ECG)。心脏导管检查显示,治疗小鼠的多个收缩和舒张血流动力学参数正常化。重要的是,完全防止了腔室扩张,并且射血分数恢复到了野生型水平。我们的结果表明,单一的全身性AAV9 SERCA2a治疗有可能为DMD提供长期的益处。SERCA2a治疗显着增强了抓地力和跑步机性能,完全防止了心肌纤维化,并使心电图正常化(ECG)。心脏导管检查显示,治疗小鼠的多个收缩和舒张血流动力学参数正常化。重要的是,完全防止了腔室扩张,并且射血分数恢复到了野生型水平。我们的结果表明,单一的全身性AAV9 SERCA2a治疗有可能为DMD提供长期的益处。SERCA2a治疗显着增强了抓地力和跑步机性能,完全防止了心肌纤维化,并使心电图正常化(ECG)。心脏导管检查显示,治疗小鼠的多个收缩和舒张血流动力学参数正常化。重要的是,完全防止了腔室扩张,并且射血分数恢复到了野生型水平。我们的结果表明,单一的全身性AAV9 SERCA2a治疗有可能为DMD提供长期的益处。射血分数恢复到野生型水平。我们的结果表明,单一的全身性AAV9 SERCA2a治疗有可能为DMD提供长期的益处。射血分数恢复到野生型水平。我们的结果表明,单一的全身性AAV9 SERCA2a治疗有可能为DMD提供长期的益处。
更新日期:2020-01-11
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