Chou Janice Yang, Zingone Adriana, Pan Chi-Jiunn
Heritable Disorders Branch, National Institute of Child Health and Human Development, Building 10, Room 9S241, NIH, Bethesda, MD 20892-1830, USA.
Eur J Pediatr. 2002 Oct;161 Suppl 1:S56-61. doi: 10.1007/s00431-002-1005-x. Epub 2002 Jul 19.
Glycogen storage disease type 1a (GSD-1a), characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and renal dysfunction, is caused by deficiencies in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. Over the last 20 years, dietary therapies have greatly improved the prognosis of GSD-1a patients. However, the underlying pathological process remains uncorrected and the efficacy of dietary treatment is frequently limited by poor compliance. Therefore, long-term complications still develop in adult patients. To develop future therapeutic approaches for GSD-1a, we have generated G6Pase-deficient (G6Pase(-/-)) mice that mimic the pathophysiology of human GSD-1a patients. To evaluate the feasibility of gene replacement therapy for this disorder, we have infused recombinant adenovirus containing murine G6Pase gene (Ad-mG6Pase) into G6Pase(-/-) mice. While only 15% of G6Pase(-/-) mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase and 90% of which lived to 3 months of age. Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored to 19% of that in G6Pase(+/+) mice at 7 through 14 post-infusion days. Ad-mG6Pase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Further, liver and kidney enlargement were less pronounced with near normal levels of glycogen depositions in both organs.
our data demonstrate that a single administration of a recombinant adenovirus vector can alleviate the clinical manifestations of glycogen storage disease type 1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy.
1a型糖原贮积病（GSD-1a）的特征为生长发育迟缓、低血糖、肝肿大、肾肿大、高脂血症、高尿酸血症和肾功能障碍，它是由葡萄糖-6-磷酸酶（G6Pase）缺乏引起的，G6Pase是葡萄糖稳态中的关键酶。在过去20年中，饮食疗法极大地改善了GSD-1a患者的预后。然而，潜在的病理过程仍未得到纠正，饮食治疗的效果常常因依从性差而受到限制。因此，成年患者仍会出现长期并发症。为了开发GSD-1a的未来治疗方法，我们培育了模拟人类GSD-1a患者病理生理学的G6Pase缺陷（G6Pase(-/-)）小鼠。为了评估该疾病基因替代疗法的可行性，我们将含有小鼠G6Pase基因的重组腺病毒（Ad-mG6Pase）注入G6Pase(-/-)小鼠体内。虽然接受葡萄糖治疗的G6Pase(-/-)小鼠只有15%存活至断奶，但当给G6Pase(-/-)小鼠注入Ad-mG6Pase时，存活率达到了100%，其中90%活到了3月龄。在注入Ad-mG6Pase后的7至14天，注入该病毒的小鼠肝脏G6Pase活性恢复到G6Pase(+/+)小鼠的19%。注入Ad-mG6Pase还极大地改善了G6Pase(-/-)小鼠的生长，并使血浆葡萄糖、胆固醇、甘油三酯和尿酸水平恢复正常。此外，肝脏和肾脏肿大不太明显，两个器官中的糖原沉积水平接近正常。
我们的数据表明，单次给予重组腺病毒载体可减轻小鼠1a型糖原贮积病的临床表现，这表明人类的这种疾病有可能通过基因治疗得到纠正。
