Replacing acid α-glucosidase in Pompe disease:: Recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers
Replacing acid α-glucosidase in Pompe disease:: Recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers
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DOI：
10.1016/j.ymthe.2004.09.017
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发表时间：
2005-01-01
影响因子：
12.4
通讯作者：
Plotz, PH
中科院分区：
文献类型：
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作者：
Raben, N;Fukuda, T;Plotz, PH
庞贝病（II 型糖原贮积病）是一种常染色体隐性遗传疾病，由溶酶体酸性 α-葡萄糖苷酶 (GAA) 缺乏导致糖原在主要在心肌和骨骼肌的溶酶体中积聚。重组人GAA（rhGAA）目前正在进行用于庞贝病酶替代疗法的临床试验。临床数据和我们的该疾病敲除模型的临床前研究结果均表明，rhGAA 在解决心肌病方面比骨骼肌肌病更有效。相比之下，另一种形式的人类 GAA 转基因酶在肝脏中组成型产生并分泌到基因敲除小鼠的血流中 (Gaa(-/-))，完全阻止了心肌糖原和骨骼肌糖原的积累。在此报告的实验中，在大量糖原已经积累后，转基因酶在输送到骨骼肌时效率要低得多。此外，转基因酶和rhGAA具有相似的治疗效果，并且都有效地清除心肌和I型肌纤维中的糖原，但不能清除II型纤维中的糖原。参与内吞作用和溶酶体酶运输的蛋白质丰度低，加上 II 型纤维中自噬增加，可能解释了治疗耐药性。
Pompe disease (type II glycogen storage disease) is an autosomal recessive disorder caused by a deficiency of lysosomal acid alpha-glucosidase (GAA) leading to the accumulation of glycogen in the lysosomes primarily in cardiac and skeletal muscle. The recombinant human GAA (rhGAA) is currently in clinical trials for enzyme replacement therapy of Pompe disease. Both clinical data and the results of preclinical studies in our knockout model of this disease show that rhGAA is much more effective in resolving the cardiomyopathy than the skeletal muscle myopathy. By contrast, another form of human GAA-transgenic enzyme constitutively produced in liver and secreted into the bloodstream of knockout mice (Gaa(-/-))-completely prevented both cardiac and skeletal muscle glycogen accumulation. In the experiments reported here, the transgenic enzyme was much less efficient when delivered to skeletal muscle after significant amounts of glycogen had already accumulated. Furthermore, the transgenic enzyme and the rhGAA have similar therapeutic effects, and both efficiently clear glycogen from cardiac muscle and type I muscle fibers, but not type II fibers. Low abundance of proteins involved in endocytosis and trafficking of lysosomal enzymes combined with increased autophagy in type II fibers may explain the resistance to therapy.