Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in α-mannosidosis mice
Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in α-mannosidosis mice
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DOI：
10.1093/hmg/ddn237
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发表时间：
2008-11-15
影响因子：
3.5
通讯作者：
Saftig, Paul
中科院分区：
文献类型：
--
作者：
Blanz, Judith;Stroobants, Stijn;Saftig, Paul
尽管主要通过酶替代疗法治疗溶酶体贮积症（lsd）取得了进展，但仅报道了将合适的溶酶体酶靶向进入大脑的有限成功。这阻碍了神经元储存的有效清除，这存在于许多这些疾病中，包括α -甘露糖病。本研究表明，重组人α -甘露糖苷酶（rhLAMAN）可以有效地治疗小鼠α -甘露糖醇病模型的神经病理学。不同剂量（25 ~ 500 U/kg）静脉给药后，rhLAMAN在组织中广泛分布，免疫组化显示注射酶的溶酶体递送。虽然低剂量（25 U/kg）在内脏组织中导致显著清除率（< 70%），但需要更高剂量才能在中枢和周围神经组织中产生明显效果。脑储存的明显减少（< 50%）需要重复高剂量注射（500 U/kg），而低剂量（250 U/kg）足以清除三叉神经节外周神经元中储存的底物。通过血脑屏障的成功转移是显而易见的，因为在海马神经元中发现了注射的酶，导致储存液泡几乎完全消失。重要的是，在未经治疗的α -甘露甘露病小鼠中，大脑中神经元储存的减少与神经运动障碍的改善相关。rhLAMAN的摄取似乎独立于甘露糖-6-磷酸受体，这与该酶的低磷酸化特征一致。这些数据表明，大剂量注射低磷酸化酶可能是有效治疗lsd累及中枢神经系统的一个有趣的选择。
Despite the progress in the treatment of lysosomal storage disorders (LSDs) mainly by enzyme replacement therapy, only limited success was reported in targeting the appropriate lysosomal enzyme into the brain. This prevents efficient clearance of neuronal storage, which is present in many of these disorders including alpha-mannosidosis. Here we show that the neuropathology of a mouse model for alpha-mannosidosis can be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of different doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a significant clearance (< 70%) in visceral tissues, higher doses were needed for a clear effect in central and peripheral nervous tissues. A distinct reduction (< 50%) of brain storage required repeated high-dose injections (500 U/kg), whereas lower doses (250 U/kg) were sufficient for clearance of stored substrates in peripheral neurons of the trigeminal ganglion. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to a nearly complete disappearance of storage vacuoles. Importantly, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seems to be independent of mannose-6-phosphate receptors, which is consistent with the low phosphorylation profile of the enzyme. These data suggest that high-dose injections of low phosphorylated enzymes might be an interesting option to efficiently treat LSDs with CNS involvement.