Enzyme Replacement Improves Ataxic Gait and Central Nervous System Histopathology in a Mouse Model of Metachromatic Leukodystrophy
Enzyme Replacement Improves Ataxic Gait and Central Nervous System Histopathology in a Mouse Model of Metachromatic Leukodystrophy
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DOI：
10.1038/mt.2008.305
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发表时间：
2009-04-01
影响因子：
12.4
通讯作者：
Gieselmann, Volkmar
中科院分区：
文献类型：
--
作者：
Matzner, Ulrich;Luellmann-Rauch, Renate;Gieselmann, Volkmar
溶酶体水解酶的遗传缺陷导致溶酶体储存性疾病(LSD)，其特征是进行性多系统病理和过早死亡。重复静脉注射缺陷酶的活性对应物，一种称为酶替代疗法(ERT)的治疗策略，逐渐成为几种不涉及中枢神经系统(CNS)的LSD的临床选择。为了评估长期ERT治疗异色性脑白质营养不良(MLD)的疗效，我们用52剂4或50 mg/kg的重组人ASA(RhASA)治疗免疫耐受芳基硫酸酯酶A(ASA)基因敲除小鼠。ERT耐受性良好，无副作用，且以剂量依赖的方式改善疾病表现。4 mg/kg剂量减少了肾脏和周围神经系统(PNS)的硫脂储存，但不影响CNS的储存，而50 mg/kg剂量的CNS也有效地减少了脑和脊髓中的硫脂储存，分别减少了34%和45%。组织学分析显示硫脂清除的区域差异。例如，在海马伞中，虽然可检测到的存储特征减少了70%，但脑干的组织病理学没有变化。两种酶剂量都使ASA基因敲除小鼠的共济失调步态正常化，证明了对主导MLD早期阶段的神经系统功能障碍的预防作用。
Inherited deficiencies of lysosomal hydrolases cause lysosomal storage diseases (LSDs) that are characterized by a progressive multisystemic pathology and premature death. Repeated intravenous injection of the active counterpart of the deficient enzyme, a treatment strategy called enzyme replacement therapy (ERT), evolved as a clinical option for several LSDs without central nervous system (CNS) involvement. To assess the efficacy of long-term ERT in metachromatic leukodystrophy (MLD), an LSD with prevailing nervous system disease, we treated immunotolerant arylsulfatase A (ASA) knockout mice with 52 doses of either 4 or 50 mg/kg recombinant human ASA (rhASA). ERT was tolerated without side effects and improved disease manifestations in a dose-dependent manner. Dosing of 4 mg/kg diminished sulfatide storage in kidney and peripheral nervous system (PNS) but not the CNS, whereas treatment with 50 mg/kg was also effective in the CNS in reducing storage in brain and spinal cord by 34 and 45%, respectively. Histological analyses revealed regional differences in sulfatide clearance. While 70% less storage profiles were detectable, for example, in the hippocampal fimbria, the histopathology of the brain stem was unchanged. Both enzyme doses normalized the ataxic gait of ASA knockout mice, demonstrating prevention of nervous system dysfunctions that dominate early stages of MLD.