Widespread and stable pancreatic gene transfer by adeno-associated virus vectors via different routes
Widespread and stable pancreatic gene transfer by adeno-associated virus vectors via different routes
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DOI：
10.2337/diabetes.55.04.06.db05-0927
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Xiao, X
中科院分区：
文献类型：
--
作者：
Wang, Z;Zhu, T;Xiao, X
糖尿病是一种流行病，并且在世界范围内呈上升趋势。基因治疗已被积极追求，但受到技术障碍和体内直接基因转移至胰腺的严重低效的限制。在这里，我们首次证明，适当的腺相关病毒（AAV）血清型与双链载体DNA盒相结合，可以通过三种不同的递送方法在成年小鼠胰腺中进行广泛且长期的体内基因转移。腹膜内和静脉内递送 AAV8 可有效转导外分泌腺泡细胞和内分泌 β 细胞，而局部胰腺导管内递送 AAV6 在本研究测试的所有 AAV 血清型中显示出对 β 细胞的最佳效率。几乎整个胰岛群都显示出基因转移，但当使用不同的递送方法和载体时，具有不同的基因转移效率和模式。重要的是，局部基因传递与胰岛素启动子相结合，可以在β细胞中进行广泛而特异性的基因表达。这些有效的新方法应该为研究糖尿病发病机制和基因治疗提供有用的工具。
Diabetes is a disease of epidemic proportions and is on the rise worldwide. Gene therapy has been actively pursued but limited by technical hurdles and profound inefficiency of direct gene transfer to the pancreas in vivo. Here, we show that, for the first time, appropriate serotypes of adeno-associated virus (AAV), coupled with a doublestranded vector DNA cassette, enable extensive and longterm in vivo gene transfer in the adult mouse pancreas by three different delivery methods. Intraperitoneal and intravenous delivery of AAV8 effectively transduced exocrine acinar cells as well as endocrine beta-cells, while local pancreatic intraductal delivery of AAV6 showed the best efficiency in the beta-cells among all AAV serotypes tested in this study. Nearly the entire islet population showed gene transfer but with distinct gene transfer efficiency and patterns when different delivery methods and vectors were used. Importantly, localized gene delivery coupled with an insulin promoter allowed extensive yet specific gene expression in the beta-cells. These effective new methods should provide useful tools to study diabetes pathogenesis and gene therapy.