Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer
Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer
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DOI：
10.1038/sj.gt.3302650
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发表时间：
2006-02-01
期刊：
影响因子：
5.1
通讯作者：
Chou, JY
中科院分区：
文献类型：
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作者：
Ghosh, A;Allamarvdasht, M;Chou, JY
Ia型糖原累积病（GSD-Ia）是由葡萄糖-6-磷酸酶-α（G6 Pase-alpha）缺乏引起的，葡萄糖-6-磷酸酶-α是一种九跨膜结构域的内质网相关蛋白，主要在肝脏和肾脏中表达。以前，我们表明，输注腺相关病毒（AAV）血清型2载体携带鼠G6蛋白酶-α（AAV 2-G6蛋白酶-α）到新生GSD-Ia小鼠未能维持他们的生活超过断奶。我们现在表明，用AAV血清型1-G6 Pase-alpha（AAV 1-G6 Pase-alpha）或AAV血清型8-G6 Pase-alpha（AAV 8-G6 Pase-alpha）新生儿输注GSD-Ia小鼠导致G6 Pase-alpha转基因的肝表达，并显著改善小鼠的存活。然而，只有AAV 1-G6 Pase-alpha可以实现显著的肾转基因表达。一种更有效的策略，其中新生儿AAV 1-G6 Pase-alpha输注之后在1周龄时进行第二次输注，在肝脏和肾脏中提供完整的功能性G6 Pase-alpha系统的持续表达，并在研究的57周长度内校正GSD-Ia小鼠中的代谢异常。这种有效利用基因治疗来纠正GSD-Ia小鼠的代谢失衡和疾病进展，为人类基因治疗的未来带来了希望。
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha), a nine-transmembrane domain, endoplasmic reticulum-associated protein expressed primarily in the liver and kidney. Previously, we showed that infusion of an adeno-associated virus (AAV) serotype 2 vector carrying murine G6Pase-alpha (AAV2-G6Pase-alpha) into neonatal GSD-Ia mice failed to sustain their life beyond weaning. We now show that neonatal infusion of GSD-Ia mice with an AAV serotype 1-G6Pase-alpha (AAV1-G6Pase-alpha) or AAV serotype 8-G6Pase-alpha (AAV8-G6Pase-alpha) results in hepatic expression of the G6Pase-alpha transgene and markedly improves the survival of the mice. However, only AAV1-G6Pase-alpha can achieve significant renal transgene expression. A more effective strategy, in which a neonatal AAV1-G6Pase-alpha infusion is followed by a second infusion at age 1 week, provides sustained expression of a complete, functional, G6Pase-alpha system in both the liver and kidney and corrects the metabolic abnormalities in GSD-Ia mice for the 57 week length of the study. This effective use of gene therapy to correct metabolic imbalances and disease progression in GSD-Ia mice holds promise for the future of gene therapy in humans.