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Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome.
Nature Genetics ( IF 30.8 ) Pub Date : 2017-Aug-01 , DOI: 10.1038/ng.3893
Grant J Logan , Allison P Dane , Claus V Hallwirth , Christine M Smyth , Emilie E Wilkie , Anais K Amaya , Erhua Zhu , Neeta Khandekar , Samantha L Ginn , Sophia H Y Liao , Sharon C Cunningham , Natsuki Sasaki , Martí Cabanes-Creus , Patrick P L Tam , David W Russell , Leszek Lisowski , Ian E Alexander

Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC.

中文翻译:

鉴定野生型AAV2基因组3'非翻译区中的肝特异性增强子-启动子活性。

基于2型腺伴随病毒(AAV2)的载体是用于基因转移和基因组编辑应用程序的强大工具。响应于人类临床试验中治疗效果的报道,最近对该系统的兴趣激增,最显着的是对于血友病B患者的治疗(参考文献3)。可以理解的是,最近的一份报告指出了AAV2整合事件与人类肝细胞癌(HCC)之间的关联,引起了关于这种关联的因果关系或附带性质以及对AAV载体安全性的影响的争议。在这里,我们描述并功能描述了野生型AAV2基因组中以前未知的肝脏特异性增强子-启动子元件,该元件位于cap基因的终止密码子(编码形成衣壳的蛋白质)和右手反向末端之间重复。
更新日期:2017-07-28
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