Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors
Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors
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DOI：
10.1038/sj.gt.3301728
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发表时间：
2002-08-01
期刊：
影响因子：
5.1
通讯作者：
Koeberl, DD
中科院分区：
文献类型：
--
作者：
Beaty, RM;Jackson, M;Koeberl, DD
Ia 型糖原贮积病 (GSD Ia) 是一种碳水化合物代谢遗传性疾病，其治疗依赖于营养支持，可推迟但无法预防 GSD Ia 的长期并发症。在 GSD Ia 的犬模型中，我们评估了静脉注射腺相关病毒 (AAV) 载体用于基因治疗的潜力。在三只受影响的犬科动物中，随着犬葡萄糖-6-磷酸酶（G6Pase）的肝脏表达，肝糖原减少。施用 AAV 载体两个月后，一只受影响的狗的空腹血糖、胆固醇、甘油三酯和乳酸恢复正常。通过对从治疗的狗中分离的肝脏 DNA 进行 Southern 印迹分析，证实多联 AAV 载体 DNA 为头对尾、头对头和尾对尾多联体。施用载体六周后，每只狗的载体 DNA 信号水平在每个细胞 1 到 5 个拷贝之间变化，这与肝脏内转导效率的变化一致。在GSD 1a的犬模型中施用AAV载体导致G6P酶持续表达以及肝脏组织学和生化参数的改善。
Therapy in glycogen storage disease type Ia (GSD Ia), an inherited disorder of carbohydrate metabolism, relies on nutritional support that postpones but fails to prevent long-term complications of GSD Ia. In the canine model for GSD Ia, we evaluated the potential of intravenously delivered adeno-associated virus (AAV) vectors for gene therapy. In three affected canines, liver glycogen was reduced following hepatic expression of canine glucose-6-phosphatase (G6Pase). Two months after AAV vector administration, one affected dog had normalization of fasting glucose, cholesterol, triglycerides, and lactic acid. Concatamerized AAV vector DNA was confirmed by Southern blot analysis of liver DNA isolated from treated dogs, as head-to-tail, head-to-head, and tail-to-tail concatamers. Six weeks after vector administration, the level of vector DNA signal in each dog varied from one to five copies per cell, consistent with variation in the efficiency of transduction within the liver. AAV vector administration in the canine model for GSD la resulted in sustained G6Pase expression and improvement in liver histology and in biochemical parameters.