Evaluation of pathological manifestations of disease in mucopolysaccharidosis VII mice after neonatal hepatic gene therapy.
Evaluation of pathological manifestations of disease in mucopolysaccharidosis VII mice after neonatal hepatic gene therapy.
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新生肝基因治疗后粘多糖贮积症VII小鼠疾病病理表现的评估。
DOI：
10.1006/mthe.2002.0809
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Ponder,KatherineParker
中科院分区：
文献类型：
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作者：
Xu,Lingfei;Mango,RobertL;Sands,MarkS;Haskins,MarkE;Ellinwood,NMatthew;Ponder,KatherineParker
粘多糖症VII(MPS VII)是由β-葡萄糖苷酸酶(GUSB)缺乏引起的一种溶酶体贮积性疾病。将表达犬GUSB的逆转录病毒载体静脉注射到新生MPS VII小鼠体内，转导了6%~35%的肝细胞，并将GUSB分泌到血液中。血清GUSB活性在600(低表达)到10000(高表达)U/ml之间稳定6个月，并用6-磷酸甘露糖适当修饰酶。平均血清GUSB活性(3531U/ml)是MPS VII小鼠在基因治疗后报告的最高长期表达。分泌酶被其他组织摄取，其平均酶活性在躯体器官为正常的13%，脑为正常的2%。低表达显著减少了肝、脾、肾、小肠、神经元和神经胶质细胞中溶酶体储存的组织病理学证据。在减少溶酶体在主动脉、心脏瓣膜、胸腺、支气管上皮、角膜和视网膜色素上皮中的存储方面，高表达似乎比低表达更有效。未来的实验将确定，与血清GUSB活性较低的动物相比，血清GUSB活性较高的逆转录病毒治疗的MPS VII小鼠是否会持续观察到更大的病理改善，以及这些是否会产生临床益处。
Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.