Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII
Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII
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DOI：
10.1073/pnas.0506892102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
Vogler, C;Levy, B;Sly, WS
酶替代疗法（ERT）有效地逆转了几种溶酶体贮积病中的贮积。然而，除了在新生儿期，脑的改善受到血脑屏障的限制。在这项研究中，我们询问是否可以通过比传统试验中使用的更高剂量的酶来克服这种障碍。我们测量了重组人β-葡糖醛酸糖苷酶（hGUS）的分布和通过在1-13周内静脉内向对重组hGUS免疫耐受的粘多糖样变性VII型小鼠施用0.3-40 mg/kg的每周剂量减少的储存。在3周内每周给予高达5 mg/kg酶的小鼠在脑膜储存中有中度减少，但在新皮层神经元中没有变化。小鼠在1周内给予20-40 mg/kg三次，除脑膜外，中枢神经系统任何区域的储存均未减少。相比之下，接受4 mg/kg/周持续13周的小鼠不仅在脑膜中，而且在顶叶新皮层和海马神经元和神经胶质中显示出清除。每周一次给予20 mg/kg持续4周的小鼠也具有减少的神经元、神经胶质和脑膜储存，并且脑中野生型hGUS活性平均为2.5%。这些结果表明，如果以比常规ERT试验中使用的剂量更高的剂量给药，并且如果在足够的时间内给予更大剂量的酶，则治疗性酶可以穿过成人粘多糖样沉积症VII型小鼠的血脑屏障递送。这些结果可能对ERT治疗伴有CNS受累的溶酶体贮积病具有重要意义。
Enzyme replacement therapy (ERT) effectively reverses storage in several lysosomal storage diseases. However, improvement in brain is limited by the blood-brain barrier except in the newborn period. In this study, we asked whether this barrier could be overcome by higher doses of enzyme than are used in conventional trials. We measured the distribution of recombinant human beta-glucuronidase (hGUS) and reduction in storage by weekly doses of 0.3-40 mg/kg administered i.v. over 1-13 weeks to mucopolysaccharidosis type VII mice immunotolerant to recombinant hGUS. Mice given up to 5 mg/kg enzyme weekly over 3 weeks had moderate reduction in meningeal storage but no change in neocortical neurons. Mice given 20-40 mg/kg three times over 1 week showed no reduction in storage in any area of the CNS except the meninges. In contrast, mice receiving 4 mg/kg per week for 13 weeks showed clearance not only in meninges but also in parietal neocortical and hippocampal neurons and glia. Mice given 20 mg/kg once weekly for 4 weeks also had decreased neuronal, glial, and meningeal storage and averaged 2.5% of wild-type hGUS activity in brain. These results indicate that therapeutic enzyme can be delivered across the blood-brain barrier in the adult mucopolysaccharidosis type VII mouse if administered at higher doses than are used in conventional ERT trials and if the larger dose of enzyme is administered over a sufficient period. These results may have important implications for ERT for lysosomal storage diseases with CNS involvement.