Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy. We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of “extra-lysosomal” events including defective autophagy and disruption of a variety of signaling pathways. Here, we report that metabolic abnormalities and energy deficit also contribute to the complexity of the pathogenic cascade. A decrease in the metabolites of the glycolytic pathway and a shift to lipids as the energy source are observed in the diseased muscle. We now demonstrate in a pre-clinical study that a recently developed replacement enzyme (recombinant human GAA; AT-GAA; Amicus Therapeutics) with much improved lysosome-targeting properties reversed or significantly improved all aspects of the disease pathogenesis, an outcome not observed with the current standard of care. The therapy was initiated in GAA-deficient mice with fully developed muscle pathology but without obvious clinical symptoms; this point deserves consideration.

庞贝病是一种糖原降解溶酶体酸α-葡萄糖苷酶（GAA）的​​缺乏症，是一种致残性多系统疾病，总是影响所有患者的骨骼肌。尽管目前可用酶替代疗法，但患者仍然负担着该疾病的沉重负担。先前我们已经表明，糖原在肌肉中的溶酶体中的逐步捕获在运动中引发了一系列“溶酶体”事件，包括自噬缺陷和各种信号通路的破坏。在这里，我们报告代谢异常和能量不足也有助于致病级联的复杂性。在患病的肌肉中观察到糖酵解途径的代谢产物减少，并转变为脂质作为能源。现在，我们在临床前研究中证明，溶酶体靶向特性大大改善的最新开发的替代酶（重组人GAA； AT-GAA； Amicus Therapeutics）可以逆转或显着改善疾病发病机理的所有方面，但未观察到结果当前的护理标准。该疗法开始于GAA缺陷型小鼠，具有完全发达的肌肉病理学但没有明显的临床症状。这一点值得考虑。该疗法开始于GAA缺陷型小鼠，具有完全发达的肌肉病理学但没有明显的临床症状。这一点值得考虑。该疗法开始于GAA缺陷型小鼠，具有完全发达的肌肉病理学但没有明显的临床症状。这一点值得考虑。