Delivery of a retroviral vector expressing human beta-glucuronidase to the liver and spleen decreases lysosomal storage in mucopolysaccharidosis VII mice.
Delivery of a retroviral vector expressing human beta-glucuronidase to the liver and spleen decreases lysosomal storage in mucopolysaccharidosis VII mice.
复制标题
将表达人β-葡萄糖醛酸酶的逆转录病毒载体递送至肝脏和脾脏可减少粘多糖贮积症VII小鼠的溶酶体储存。
DOI：
10.1006/mthe.2000.0121
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Ponder,KP
中科院分区：
文献类型：
--
作者：
Gao,C;Sands,MS;Haskins,ME;Ponder,KP
粘多糖沉积症VII（MPS VII）由β-葡萄糖醛酸酶（β-gluc）缺乏引起，由于无法降解糖胺聚糖而导致溶酶体蓄积。将β-gluc基因转移到肝脏中可减少肝脏病理学以及通过摄取分泌蛋白在其他器官中的储存。在肝细胞复制期间，将表达人β-gluc cDNA的基于Moloney小鼠白血病的逆转录病毒载体血管内注射到MPS VII小鼠中，通过肌肉注射瞬时表达肝细胞生长因子（Ad.CMV.HGF）的腺病毒载体诱导肝细胞复制。该程序导致约1%的肝细胞转导，1%的正常肝酶活性，以及3.5个月时肝脏中溶酶体蓄积的减少。令人惊讶的是，接受不含HGF的逆转录病毒载体的对照组在肝脏中具有非实质细胞的转导，在2个月但不是3.5个月时肝脏中具有显著水平的酶和RNA，并且在3.5个月时具有减少的溶酶体储存。在脾的复制细胞中也实现了转导，其中溶酶体储存减少。使用不含生长因子的逆转录病毒载体的方法可能会暂时减少人类肝脏和脾脏中的溶酶体储存。添加HGF可用于增强和延长基因转移。
Mucopolysaccharidosis VII (MPS VII) is caused by β-glucuronidase (β-gluc) deficiency and results in lysosomal storage due to the inability to degrade glycosaminoglycans. Transfer of a β-gluc gene into the liver reduces hepatic pathology as well as storage in other organs via uptake of secreted protein. A Moloney murine leukemia-based retroviral vector expressing the human β-gluc cDNA was injected intravascularly into MPS VII mice during hepatocyte replication, which was induced with im injection of an adenoviral vector that transiently expressed hepatocyte growth factor (Ad.CMV.HGF). This procedure resulted in transduction of ~1% of hepatocytes, 1% of normal liver enzyme activity, and a reduction in lysosomal storage in the liver at 3.5 months. Surprisingly, controls that received retroviral vector without HGF had transduction of non-parenchymal cells in the liver, significant levels of enzyme and RNA in the liver at 2 but not 3.5 months, and reduced lysosomal storage at 3.5 months. Transduction was also achieved in the replicating cells of the spleen, where lysosomal storage was reduced. An approach using a retroviral vector without a growth factor might temporarily reduce lysosomal storage in the liver and spleen in humans. Addition of HGF might be used to augment and prolong gene transfer.