Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs
Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs
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DOI：
10.1073/pnas.192353499
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Haskins, ME
中科院分区：
文献类型：
--
作者：
Ponder, KP;Melniczek, JR;Haskins, ME
在2-3日龄时，向粘多糖病VII （MPS VII）犬静脉注射表达犬β -葡糖醛酸酶（cGUSB）的逆转录病毒载体（RV）。5只动物单独接受RV， 2只狗在RV之前接受肝细胞生长因子（HGF），以提高转导效率。在正常肝脏生长过程中，转导的肝细胞克隆扩增，并分泌含有甘露糖6-磷酸的酶。rv治疗犬的血清GUSB活性在正常水平上稳定了14个月，HGF/ rv治疗犬的血清GUSB活性在正常水平上稳定了17个月，是正常水平的67倍。两只接受rv治疗的狗在6个月时其他器官的GUSB活性为正常的1.5-60%，这可能是因为甘露糖6-磷酸受体从血液中摄取酶。未经治疗的MPS VII犬在6个月时体重为正常的50%。MPS VII型狗在6个月后不能行走或站立，并逐渐发展为眼睛和心脏疾病。经RV和HGF/RV处理的MPS VII犬的体重分别达到正常体重的87%和84%。由于骨和关节异常的改善，治疗后的动物在6-17个月的任何评估时间都可以跑步，角膜混浊很少或没有，二尖瓣没有增厚。尽管GUSB表达较高，但HGF/ rv治疗犬的临床改善与rv治疗犬相似。这是基因治疗在大型动物中首次成功应用于预防溶酶体贮积病的临床表现。
Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2-3 days of age with a retroviral vector (RV) expressing canine beta-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5-60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6-17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.