Meena Naresh Kumar, Ralston Evelyn, Raben Nina, Puertollano Rosa
Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA.
Mol Ther Methods Clin Dev. 2020 Jun 10;18:199-214. doi: 10.1016/j.omtm.2020.05.026. eCollection 2020 Sep 11.
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.
庞贝病是一种因溶酶体酸性α-葡萄糖苷酶（GAA）缺乏而导致的疾病，是一种致残性多系统疾病，所有患者都会出现骨骼肌受累。尽管目前有酶替代疗法，但患者仍承受着沉重的疾病负担。我们之前已经表明，肌肉中糖原在溶酶体中的渐进性蓄积引发了一系列“溶酶体外”事件，包括自噬缺陷和多种信号通路的破坏。在此，我们报告代谢异常和能量缺乏也加剧了致病级联反应的复杂性。在患病肌肉中观察到糖酵解途径代谢物减少，并转向以脂质作为能量来源。我们现在在一项临床前研究中证明，一种最近开发的具有显著改善的溶酶体靶向特性的替代酶（重组人GAA；AT-GAA；阿美icus治疗公司）逆转或显著改善了疾病发病机制的各个方面，这一结果在当前的标准治疗中未观察到。该疗法在GAA缺乏且肌肉病理完全发展但无明显临床症状的小鼠中开始；这一点值得考虑。
