Pompe disease is a metabolic myopathy due to acid alpha-glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha-glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients’ cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N-acetylcysteine, idebenone, resveratrol, edaravone) improved alpha-glucosidase activity in rhGAA-treated cells, enhanced enzyme processing, and improved mannose-6-phosphate receptor localization. When co-administered with rhGAA, antioxidants improved alpha-glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder.

中文翻译：

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纠正氧化应激可增强庞贝病的酶替代疗法

庞贝病是一种由于酸性α-葡萄糖苷酶缺乏而导致的代谢性肌病。除了糖原储存之外，细胞功能的继发性失调，例如自噬和氧化应激，也会导致该疾病的病理生理学。我们测试了氧化应激是否会影响重组人 α-葡萄糖苷酶 (rhGAA) 酶替代疗法（目前庞贝病患者的护理标准），以及纠正氧化应激是否可能有利于 rhGAA 疗法。我们发现庞贝病小鼠模型的组织和患者细胞中的氧化应激水平升高。在细胞中，应激水平与 rhGAA 纠正酶缺乏的能力呈负相关。抗氧化剂（N-乙酰半胱氨酸、艾地苯醌、白藜芦醇、依达拉奉）可改善 rhGAA 处理细胞中的 α-葡萄糖苷酶活性，增强酶加工，并改善 6-磷酸甘露糖受体定位。当与 rhGAA 共同给药时，抗氧化剂提高了庞贝病小鼠模型组织中的 α-葡萄糖苷酶活性。这些结果表明，氧化应激影响庞贝病酶替代疗法的功效，并且控制继发性异常可能是提高该疾病治疗功效的策略。