Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice.
Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice.
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DOI：
10.1074/jbc.m112.438663
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发表时间：
2013-01-18
期刊：
影响因子：
--
通讯作者：
LeBowitz JH
中科院分区：
文献类型：
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作者：
Maga JA;Zhou J;Kambampati R;Peng S;Wang X;Bohnsack RN;Thomm A;Golata S;Tom P;Dahms NM;Byrne BJ;LeBowitz JH
背景资料：酸性α-葡萄糖苷酶是庞贝氏症的一种酶替代疗法，当依赖于磷酸甘露糖残基时，其对溶酶体的靶向性较差。结果：IGF-II与酸性α-葡萄糖苷酶融合后，能显著提高Pompe小鼠对胰岛素的摄取和糖原的清除。结论：增强与阳离子非依赖性甘露糖6-磷酸受体（CI-MPR）的结合能够改善庞贝氏症小鼠的糖原清除。意义：BMN 701目前正在人体临床研究中进行庞贝氏症的测试。我们使用了一种基于肽的靶向系统来改善酸性α-葡萄糖苷酶（GAA）的溶酶体递送，这种酶在庞贝氏症患者中缺乏。将人GAA与糖基化非依赖性溶酶体靶向（GILT）标签融合，该标签含有胰岛素样生长因子II的一部分，以产生对阳离子非依赖性甘露糖6-磷酸受体具有高亲和力的活性嵌合酶。GILT标记的GAA被L 6成肌细胞摄取的效率比重组人GAA（rhGAA）高约25倍。一旦递送至溶酶体，GILT标记的GAA的成熟形式与rhGAA无法区分，并且以与rhGAA无法区分的半衰期持续存在。在庞贝氏症小鼠模型中，GILT标记的GAA在清除许多骨骼肌组织中的糖原方面比rhGAA显著更有效。GILT标记的GAA酶可为庞贝氏症患者提供改善的酶替代疗法。
Background: Acid α-glucosidase, an enzyme replacement therapy for Pompe disease, is poorly targeted to lysosomes when relying on phosphomannose residues. Results: Fusing IGF-II to acid α-glucosidase resulted in more efficient uptake and glycogen clearance from muscle of Pompe mice. Conclusion: Enhanced binding to the cation-independent mannose 6-phosphate receptor (CI-MPR) enabled improved glycogen clearance in Pompe mice. Significance: BMN 701 is now being tested for Pompe disease in human clinical studies. We have used a peptide-based targeting system to improve lysosomal delivery of acid α-glucosidase (GAA), the enzyme deficient in patients with Pompe disease. Human GAA was fused to the glycosylation-independent lysosomal targeting (GILT) tag, which contains a portion of insulin-like growth factor II, to create an active, chimeric enzyme with high affinity for the cation-independent mannose 6-phosphate receptor. GILT-tagged GAA was taken up by L6 myoblasts about 25-fold more efficiently than was recombinant human GAA (rhGAA). Once delivered to the lysosome, the mature form of GILT-tagged GAA was indistinguishable from rhGAA and persisted with a half-life indistinguishable from rhGAA. GILT-tagged GAA was significantly more effective than rhGAA in clearing glycogen from numerous skeletal muscle tissues in the Pompe mouse model. The GILT-tagged GAA enzyme may provide an improved enzyme replacement therapy for Pompe disease patients.