Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver.

中文翻译：

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糖原贮积病小鼠和犬模型中基因治疗后肝肿瘤的发病机制。

糖原贮积病Ia型（GSD Ia）是由葡萄糖6磷酸酶（G6Pase）催化亚基基因（G6PC）突变引起的。GSD Ia并发症包括具有肝细胞癌（HCC）形成风险的肝细胞腺瘤（HCA）。在患有GSD Ia的成年小鼠中评估了使用含锌指核酸酶（ZFN）和G6PC供体转基因的腺相关病毒（AAV）载体进行的基因组编辑。尽管小鼠肝脏表达G6Pase，但在施用AAV载体后仍发生HCA和HCC。有趣的是，在肿瘤中几乎无法检测到载体基因组，但在相邻的肝脏中仍保持相对较高的水平（p <0.01）。与邻近的肝脏相比，肿瘤中的G6Pase活性降低了（p <0.01）。此外，经AAV-G6Pase载体治疗的GSD Ia犬患上的HCC的G6Pase活性较低（p <0。01）与邻近肝脏比较。小鼠中的AAV整合和肿瘤标志物分析表明，肿瘤是由潜在疾病引起的，而不是由载体给药引起的。与人GSD Ia相关的HCA和HCC相似，小鼠和犬肿瘤也不表达升高的甲胎蛋白。综上所述，这些结果表明，AAV介导的基因治疗不仅可以纠正肝G6Pase缺乏症，而且还具有抑制GSD Ia肝中HCA和HCC的潜力。