Enzyme replacement reduces neuropathology in MPS IIIA dogs
Enzyme replacement reduces neuropathology in MPS IIIA dogs
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DOI：
10.1016/j.nbd.2011.04.014
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发表时间：
2011-08-01
影响因子：
6.1
通讯作者：
Hemsley, Kim M.
中科院分区：
文献类型：
--
作者：
Crawley, Allison C.;Marshall, Neil;Hemsley, Kim M.
进行性神经退行性溶酶体贮积症IIIA型粘多糖贮积症（MPS IIIA）尚无治疗方法，该疾病是由于功能性N-磺基葡糖胺磺基水解酶（SGSH）缺乏所致，随后部分降解的硫酸乙酰肝素和二次储存化合物（包括GM 2和GM 3神经节苷脂和未酯化胆固醇）蓄积。大脑是一个主要的病理部位，受影响的儿童表现出进行性认知能力下降和过早死亡。在本研究中，6只MPS IIIA犬从出生至8或12周龄（1 mg/kg，最高5 mg）接受静脉注射重组人GSH（rhGSH），随后每周或每两周一次脑脊液内注射3或15 mg rhGSH（或溶剂），直至23周龄。所有的狗都完成了方案，没有发生任何事件，并且对rhGSH递送没有临床相关的细胞或体液免疫应答。免疫组织化学证实rhSGSH递送到大脑的广泛区域，并且串联质谱显示硫酸乙酰肝素衍生的二糖的相对水平明显呈剂量依赖性降低，在较高剂量下许多大脑区域中的底物接近正常化。二次储存的GM 3神经节苷脂和未酯化的胆固醇，使用组织学方法测定，也减少了剂量依赖性的方式，是激活的小胶质细胞的数量。我们已经证明，通过脑脊液内注射rhGSH对这种进行性神经退行性疾病进行症状前治疗，可介导MPS IIIA模型中神经病理学的高度显著降低，因此指示在MPS IIIA患者中进行这种治疗方法的临床试验。皇冠版权所有（C）2011由爱思唯尔公司出版。All rights reserved.
There is no treatment for the progressive neurodegenerative lysosomal storage disorder mucopolysaccharidosis type IIIA (MPS IIIA), which occurs due to a deficiency of functional N-sulfoglucosamine sulfohydrolase (SGSH), with subsequent accumulation of partially-degraded heparan sulfate and secondarily-stored compounds including GM2 and GM3 gangliosides and unesterified cholesterol. The brain is a major site of pathology and affected children exhibit progressive cognitive decline and early death. In the present study, six MPS IIIA dogs received intravenous recombinant human SGSH (rhSGSH) from birth to either 8 or 12 weeks of age (1 mg/kg, up to 5 mg), with subsequent intra-cerebrospinal fluid injection of 3 or 15 mg rhSGSH (or vehicle) on a weekly or fortnightly basis to 23 weeks of age. All dogs completed the protocol without incident, and there was no clinically-relevant cellular or humoral immune response to rhSGSH delivery. Immunohistochemistry demonstrated rhSGSH delivery to widespread regions of the brain, and tandem mass spectrometry revealed an apparent dose-dependent decrease in the relative level of a heparan sulfate-derived disaccharide, with near normalization of substrate in many brain regions at the higher dose. Secondarily-stored GM3 ganglioside and unesterified cholesterol, determined using histological methods, were also reduced in a dose-dependent manner, as was the number of activated microglia. We have demonstrated that pre-symptomatic treatment of this progressive neurodegenerative disorder via intra-cerebrospinal fluid injection of rhSGSH mediates highly significant reductions in neuropathology in this MPS IIIA model and clinical trials of this treatment approach in MPS IIIA patients are therefore indicated. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved.