Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice
Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice
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DOI：
10.1016/j.ymgme.2006.10.005
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发表时间：
2007-03-01
影响因子：
3.8
通讯作者：
Hopwood, John J.
中科院分区：
文献类型：
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作者：
Hemsley, Kim M.;King, Barbara;Hopwood, John J.
目前，对于影响大脑的溶酶体贮积症（LSD），还没有广泛可用的、安全有效的治疗方法。本研究采用自然发病的粘多糖沉积症IIIA型（NIPS IIIA）或Sanfilippo综合征小鼠模型，评价经小脑延髓池（CM）反复注射重组人磺酰胺酶（rhSGSH）对中枢神经系统（CNS）病理和行为功能的影响。小鼠每两周或每月接受Lip至七次rhSGSH注射（每次注射5-20 μ g rhSGSH）或载体。在脑（LIP降至62%，与溶剂处理的MPS IIIA小鼠相比降低）和脊髓（降低高达71%）中观察到硫酸乙酰肝素衍生的单硫酸化二糖水平的密切依赖性降低。超微结构检查显示，减少溶酶体囊泡形成在各种类型的细胞和更少的（泛素阳性）轴突球状体中观察到几个脑区。生化变化伴随着行为的改善，特别是在小鼠治疗更频繁。在治疗的动物中观察到对rhSGSH的体液免疫应答。因此，CM内注射溶酶体酶可能是治疗这种和其他可能影响大脑的LSD的CNS效应的立即适用的方法。皇冠版权所有（c）2006由爱思唯尔公司出版。All rights reserved.
At present, there is no widely available, safe and effective treatment for lysosomal storage disorders (LSD) that affect the brain. We have used a naturally Occurring mouse model of mucopolysaccharidosis type IIIA (NIPS IIIA) or Sanfilippo syndrome, to evaluate the effect of repeated injection of recombinant human sulfamidase (rhSGSH) into the cerebrospinal fluid via the cisterna magna (CM) on central nervous system (CNS) pathology and behavioral function. Mice received Lip to seven injections of rhSGSH (5-20 mu g rhSGSH per injection) or vehicle on a fortnightly or monthly basis. A close-dependent reduction in the level of a heparan sulfate-derived mono-sulfated disaccharide was observed within the brain (LIP to 62%, reduction compared with vehicle-treated MPS IIIA mice) and spinal cord (up to 71% reduction). Ultrastructural examination revealed a reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) axonal spheroids were observed in several brain regions. The biochemical changes were accompanied by improved behavior, particularly in mice-treated more frequently. Alhumoral immune response to rhSGSH was observed in treated animals. Intra-CM injection of lysosomal enzyme may therefore represent an immediately applicable method of treating the CNS effects of this and potentially other LSD that affect the brain. Crown Copyright (c) 2006 Published by Elsevier Inc. All rights reserved.