Treatment of Duchenne Muscular Dystrophy with the Muscle Calcium Pump

项目摘要 胞浆钙超载是Duchenne型肌营养不良症（DMD）的关键致病机制， 致命的肌肉衰弱病胞质钙离子升高触发蛋白水解和肌细胞死亡。 肌浆网/内质网钙ATP酶2a（SERCA 2a）是一种钙泵， 骨骼肌和心肌中的钙。不幸的是，DMD肌肉中的SERCA 2a水平降低。 增强SERCA 2a表达可以恢复细胞溶质钙稳态并减少肌肉疾病， DMD为了探索这种新的治疗方法，我们产生了一种腺相关病毒载体（AAV）， SERCA2a。我们通过尾静脉将AAV SERCA 2a载体注射到mdx小鼠中，mdx小鼠是最常用的小鼠。 DMD模型。治疗显著改善了骨骼肌力量和心脏功能。翻译我们的 对于大型哺乳动物的研究结果，我们建议在有症状的DMD犬中测试AAV SERCA 2a治疗， DMD的大型动物模型。我们假设AAV SERCA 2a治疗可以显著增强细胞内的细胞溶质， 钙去除和改善骨骼肌和心脏疾病的营养不良的狗。为了验证这个假设， 我们会致力达致两个目标。在我们的第一个目标中，我们将测试区域AAV SERCA 2a治疗是否可以 改善肢体肌肉疾病，改善功能。区域治疗具有改善生活的潜力 患者的质量，尤其是晚期患者。在我们的第二个目标中，我们将测试系统性AAV是否 SERCA 2a治疗可导致受影响犬的全身改善。DMD会影响身体的所有肌肉。 全身肌肉治疗将产生最大的保护。总之，我们的研究将产生 为未来的人体试验提供关键的大型动物数据。

Project Abstract Cytosolic calcium overload is a pivotal pathogenic mechanism in Duchenne muscular dystrophy (DMD), a lethal debilitating muscle disease. Elevated cytosolic calcium triggers proteolysis and muscle cell death. Sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is the calcium pump that removes cytosolic calcium in both skeletal and cardiac muscle. Unfortunately, the SERCA2a level is reduced in DMD muscle. Enhancing SERCA2a expression may restore cytosolic calcium homeostasis and reduce muscle disease in DMD. To explore this novel therapy, we generated an adeno-associated viral vector (AAV) to express SERCA2a. We injected the AAV SERCA2a vector via the tail vein to mdx mice, the most commonly used DMD model. Treatment significantly improved skeletal muscle force and heart function. To translate our findings to large mammals, we propose to test AAV SERCA2a therapy in symptomatic DMD dogs, the best large animal model for DMD. We hypothesize that AAV SERCA2a therapy can significantly enhance cytosolic calcium removal and ameliorate skeletal muscle and heart disease in dystrophic dogs. To test this hypothesis, we will pursue two specific aims. In our first aim, we will test whether regional AAV SERCA2a therapy can ameliorate limb muscle disease and improve function. Regional therapy holds potential to improve the life quality of patients, especially these at late-stage. In our second aim, we will test whether systemic AAV SERCA2a therapy can lead to bodywide improvement in affected dogs. DMD affects all muscles in the body. Whole body muscle therapy will result in maximal protection. In summary, our proposed studies will generate the critical large animal data for a future human trial.