Enhancing transduction of the liver by adeno-associated viral vectors.
Enhancing transduction of the liver by adeno-associated viral vectors.
复制标题
通过腺相关病毒向量增强肝脏的转导。
作者：
在腺相关病毒载体（AAV）介导的基因转移过程的不同阶段，发现了许多不同的因素影响小鼠肝细胞转导。其中最重要的是病毒衣壳蛋白。自互补（sc） AAV假型与衣壳来自血清型8或rh。与AAV7衣壳包装的载体相比，在给定的载体剂量下，AAV7介导的肝细胞转导能力提高了四倍。在所有血清型中，载体剂量与转基因表达之间几乎呈线性关系，载体剂量低至1×107vg/小鼠（4×108vg/kg）介导人类FIX （hFIX）表达的治疗水平。性别显著影响scAAV介导的转基因表达，在雄性小鼠中观察到的表达水平是雌性小鼠的两倍。用蛋白酶体抑制剂硼替佐米预处理小鼠，雌性小鼠中scAAV介导的hFIX表达从4±0.6μg/ml增加到9±2μg/ml，但雄性小鼠中该药物的作用不太明显。用AAV载体转染基因10-20周后，将小鼠暴露于腺病毒中，通过增加原病毒mRNA的水平，使AAV转基因表达增加两倍。因此，优化AAV基因转移过程中的各个步骤，可以进一步增强AAV介导的转基因表达效力，从而增加基因治疗成功的概率。
A number of distinct factors acting at different stages of the adeno-associated virus vector (AAV)-mediated gene transfer process were found to influence murine hepatocyte transduction. Foremost amongst these was the viral capsid protein. Self complementary (sc) AAV pseudotyped with capsid from serotype 8 or rh.10 mediated four-fold greater hepatocyte transduction for a given vector dose when compared to vector packaged with AAV7 capsid. An almost linear relationship between vector dose and transgene expression was noted for all serotypes with vector doses as low as 1×107vg/mouse (4×108vg/kg) mediating therapeutic levels of human FIX (hFIX) expression. Gender significantly influenced scAAV mediated transgene expression with two fold higher levels of expression observed in male compared to female mice. Pretreatment of mice with the proteasome inhibitor bortezomib, increased scAAV mediated hFIX expression from 4±0.6μg/ml to 9±2μg/ml in female mice although the effect of this agent was less profound in males. Exposure of mice to adenovirus 10-20 weeks after gene transfer with AAV vectors augmented AAV transgene expression two-fold by increasing the level of proviral mRNA. Hence, optimization of individual steps in the AAV gene transfer process can further enhance the potency of AAV-mediated transgene expression, thus increasing the probability of successful gene therapy.
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影响因子：
5.4
作者：
Akache, Bassel;Grimm, Dirk;Kay, Mark A.
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Kay, Mark A.
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3.1
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Davidoff, AM;Ng, CYC;Nathwani, AC
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15.9
作者：
FOURNIER, S;DELESPESSE, G;SARFATI, M
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SARFATI, M
影响因子：
5.1
作者：
McCarty, DM;Fu, H;Samulski, RJ
通讯作者：
Samulski, RJ
影响因子：
168.9
作者：
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通讯作者：
During, Matthew J.