Glycosylation-independent taraetina enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice
Glycosylation-independent taraetina enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice
复制标题
DOI：
10.1073/pnas.0308728100
复制
发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
LeBowitz, JH;Grubb, JH;Sly, WS
酶替代疗法是治疗溶酶体贮积病的既定方法。输注的治疗酶通过与识别酶上碳水化合物部分（例如甘露糖和甘露糖 6-磷酸）的细胞表面受体相互作用，靶向受影响细胞的溶酶体。我们测试了另一种基于肽的靶向系统，用于在小鼠粘多糖贮积症 VII 型 (MPS VII) 模型中将酶递送至溶酶体。该策略取决于胰岛素样生长因子 II (IGF-II) 片段与双功能 IGF-II 阳离子依赖性甘露糖 6-磷酸受体上的 IGF-II 结合位点的相互作用。包含与人β-葡萄糖醛酸酶C末端融合的成熟人IGF-II的一部分的嵌合蛋白以不依赖甘露糖6-磷酸的方式被MPS VII成纤维细胞摄取，并且其摄取通过添加IGF-II而被抑制。此外，标记的酶被有效地递送至 MPS VII 小鼠的临床重要组织，并有效逆转储存病理学。标记的酶能够减少肾小球足细胞和成骨细胞中的储存，其剂量与未标记的酶的效果要差得多。这种基于肽的、不依赖于糖基化的溶酶体靶向系统可以增强酶替代疗法。用于某些人类溶酶体贮积病。
Enzyme-replacement therapy is an established means of treating lysosomal storage diseases. infused therapeutic enzymes are targeted to lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate, on the enzymes. We have tested an alternative, peptide-based targeting system for delivery of enzymes to lysosomes in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy depends on the interaction of a fragment of insulin-like growth factor II (IGF-II), with the IGF-II binding site on the bifunctional, IGF-II cation-independent mannose 6-phosphate receptor. A chimeric protein containing a portion of mature human IGF-II fused to the C terminus of human beta-glucuronidase was taken up by MPS VII fibroblasts in a mannose 6-phosphate-independent manner, and its uptake was inhibited by the addition of IGF-II. Furthermore, the tagged enzyme was delivered effectively to clinically significant tissues in MPS VII mice and was effective in reversing the storage pathology. The tagged enzyme was able to reduce storage in glomerular podocytes and osteoblasts at a dose at which untagged enzyme was much less effective. This peptide-based, glycosylation-independent lysosomal targeting system may enhance enzyme-replacement therapy. for certain human lysosomal storage diseases.