Long circulating enzyme replacement therapy rescues bone pathology in mucopolysaccharidosis VII murine model
Long circulating enzyme replacement therapy rescues bone pathology in mucopolysaccharidosis VII murine model
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DOI：
10.1016/j.ymgme.2012.07.002
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发表时间：
2012-09-01
影响因子：
3.8
通讯作者：
Sly, William S.
中科院分区：
文献类型：
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作者：
Rowan, Daniel J.;Tomatsu, Shunji;Sly, William S.
粘多糖病（MPS） VII型是由溶酶体酶-葡萄糖醛酸酶（GUS）缺乏引起的溶酶体贮积病，导致糖胺聚糖（GAGs）的积累。酶替代疗法（ERT）可以有效清除内脏中的GAG储存。最近的研究表明，一种化学修饰形式的GUS （PerT-GUS）可以逃脱甘露糖6-磷酸和甘露糖受体的清除，并表现出长时间的循环，比天然GUS更有效地降低了中枢神经系统的储存。由于生长板的无血管性，骨内储存的清除受到限制。为了评估长循环PerT-GUS减轻骨骼病理的有效性，我们从5周龄开始用PerT-GUS或天然GUS治疗MPS VII小鼠12周，并使用显微ct、x线照片和定量组织病理学分析来评估骨骼。显微ct结果显示，PerT-GUS治疗小鼠的骨密度显著降低。组织病理学分析还显示，与天然GUS处理小鼠相比，PerT-GUS处理小鼠的储存材料减少，生长板更有组织。从出生到57周，PerT-GUS长期治疗也显著改善了显微ct、x线照片和定量组织病理学分析显示的骨病变。总之，长循环的PerT-GUS对骨病变和中枢神经系统受累的抢救有重要影响。(C) 2012爱思唯尔公司版权所有。
Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by deficiency of the lysosomal enzyme beta-glucuronidase (GUS), leading to accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) effectively clears GAG storage in the viscera. Recent studies showed that a chemically modified form of GUS (PerT-GUS), which escaped clearance by mannose 6-phosphate and mannose receptors and showed prolonged circulation, reduced CNS storage more effectively than native GUS. Clearance of storage in bone has been limited due to the avascularity of the growth plate.To evaluate the effectiveness of long-circulating PerT-GUS in reducing the skeletal pathology, we treated MPS VII mice for 12 weeks beginning at 5 weeks of age with PerT-GUS or native GUS and used micro-CT, radiographs, and quantitative histopathological analysis for assessment of bones.Micro-CT findings showed PerT-GUS treated mice had a significantly lower BMD. Histopathological analysis also showed reduced storage material and a more organized growth plate in PerT-GUS treated mice compared with native GUS treated mice. Long term treatment with PerT-GUS from birth up to 57 weeks also significantly improved bone lesions demonstrated by micro-CT, radiographs and quantitative histopathological assay.In conclusion, long-circulating PerT-GUS provides a significant impact to rescue of bone lesions and CNS involvement. (C) 2012 Elsevier Inc. All rights reserved.