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Research Article

基因治疗后庞贝氏病小鼠模型中自噬积累的减少

卷 19, 期 3, 2019

页: [197 - 207] 页: 11

弟呕挨: 10.2174/1566523219666190621113807

摘要

背景：庞贝病是一种致命的神经肌肉疾病，由酸性α-葡萄糖苷酶（一种导致溶酶体糖原降解的酶）不足引起。目前，庞贝氏病唯一批准的治疗方法是酶替代疗法（ERT），它可以提高患者的生存率，但不能完全纠正骨骼肌的病理。 ERT无法纠正骨骼肌病理，因为不依赖阳离子的低甘露糖-6-磷酸受体的丰度和自噬积累抑制了酶到达溶酶体。因此，庞贝病需要一种更有效地靶向骨骼肌病理的疗法，例如腺伴随病毒（AAV）。 目的：该项目的目标是提供由组织限制性启动子驱动的rAAV9-coGAA载体，以有效地转导骨骼肌并纠正自噬。 方法：因此，将rAAV9-coGAA分三剂静脉内递送给12周龄的Gaa-/-小鼠。注射后1个月，对骨骼肌进行生化和组织学分析以寻找自噬相关标记。 结果：在最高剂量下，GAA酶活性和空泡得分达到治疗水平。此外，通过自噬相关蛋白的免疫荧光和蛋白质印迹分析，可以观察到自噬体（AP）积累的分辨率。最后，与3个月时相比，出生时接受治疗的小鼠表现出了GAA表达的持久性以及溶酶体和AP的消退。 结论：总之，单次系统性注射rAAV9-coGAA可改善液泡积累并防止自噬失调。

关键词: 庞贝病，自噬，基因治疗，rAAV，GAA，骨骼肌。

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