Chemically modified β-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII
Chemically modified β-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII
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化学修饰的 β-葡萄糖醛酸酶穿过血脑屏障并清除小鼠粘多糖贮积症 VII 中的神经元储存
DOI：
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发表时间：
2008
影响因子：
11.1
通讯作者：
W. Sly
中科院分区：
文献类型：
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作者：
J. Grubb;C. Vogler;B. Levy;N. Galvin;Yun Tan;W. Sly
酶替代疗法已成功地用于许多溶酶体贮积病。然而，脑储存的校正受到注入的酶不能穿过血脑屏障的限制。新生小鼠是一个例外，因为重组酶是在甘露糖6-磷酸受体介导的转胞吞作用后递送到新生小鼠脑中的。2周龄后，进入这条路线的机会非常有限。最近，几项研究表明，多次注入高剂量的酶可以部分清除成人大脑中的储存。这些结果提出了一个问题，即反复高剂量的酶对脑储存的校正是否取决于甘露糖6-磷酸受体介导的摄取，或者当脑毛细血管长时间暴露于高水平的循环酶时，酶是否通过另一种途径进入脑储存。为了解决这个问题，我们使用了一种酶，其碳水化合物依赖性受体介导的摄取被化学修饰灭活。用偏高碘酸钠处理人β-葡萄糖醛酸糖苷酶（GUS），然后用硼氢化钠还原（PerT-GUS），消除了培养细胞中甘露糖6-磷酸和甘露糖受体的摄取，并显著减缓了其血浆清除率，从t1/2 <10 min降至18 h。令人惊讶的是，PerT-GUS每周输注12周在清除中枢神经系统储存方面比相同剂量的天然GUS更有效。事实上，PerT-GUS几乎完全逆转了新皮层和海马神经元的储存。长循环酶对神经元储存的这种增强的校正，其靶向没有已知的受体，这表明可能在治疗上利用穿过血脑屏障的递送系统。
Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood–brain barrier. The newborn mouse is an exception because recombinant enzyme is delivered to neonatal brain after mannose 6-phosphate receptor-mediated transcytosis. Access to this route is very limited after 2 weeks of age. Recently, several studies showed that multiple infusions of high doses of enzyme partially cleared storage in adult brain. These results raised the question of whether correction of brain storage by repeated high doses of enzyme depends on mannose 6-phosphate receptor-mediated uptake or whether enzyme gains access to brain storage by another route when brain capillaries are exposed to prolonged, high levels of circulating enzyme. To address this question, we used an enzyme whose carbohydrate-dependent receptor-mediated uptake was inactivated by chemical modification. Treatment of human β-glucuronidase (GUS) with sodium metaperiodate followed by sodium borohydride reduction (PerT-GUS) eliminated uptake by mannose 6-phosphate and mannose receptors in cultured cells and dramatically slowed its plasma clearance from a t½ of <10 min to 18 h. Surprisingly, PerT-GUS infused weekly for 12 weeks was more effective in clearing central nervous system storage than native GUS at the same dose. In fact, PerT-GUS resulted in almost complete reversal of storage in neocortical and hippocampal neurons. This enhanced correction of neuronal storage by long-circulating enzyme, which targets no known receptor, suggests a delivery system across the blood–brain barrier that might be exploited therapeutically.
鼠粘多糖贮积症 VIL：治疗对溶酶体贮积病模型表型、临床病程和病理学的影响。
DOI：
10.1007/s10024001-0079-1
发表时间：
2001
期刊：
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.
影响因子：
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作者：
Vogler,C;Barker,J;Sands,MS;Levy,B;Galvin,N;Sly,WS
通讯作者：
Sly,WS