Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction.
Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction.
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鸟氨酸转氨甲酰酶基因校正后重组腺相关病毒在小鼠肝脏中的整合位点。
DOI：
10.1089/hum.2012.112
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发表时间：
2013
影响因子：
4.2
通讯作者：
Gao,Guangping
中科院分区：
文献类型：
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作者：
Zhong,Li;Malani,Nirav;Li,Mengxin;Brady,Troy;Xie,Jun;Bell,Peter;Li,Shaoyong;Jones,Haven;Wilson,JamesM;Flotte,TerenceR;Bushman,FredericD;Gao,Guangping
重组腺相关病毒（raav）已在人类和其他大型哺乳动物中进行了试验，未发生不良事件。然而，一项对小鼠粘多糖病VII矫正的研究显示，rAAV在肝细胞癌（HCC）细胞中的dlk1 - dio3位点反复整合，提示可能存在插入性突变。相比之下，另一项研究发现rAAV整合与HCC没有关联，这提出了肝脏转化与dlk1 - dio3整合之间普遍关联的问题。本文作者报道，在rAAV治疗的鸟氨酸转甲氨基酰基酶（Otc）缺陷小鼠中，可以在肝结节/肿瘤标本中检测到四个整合位点indlk1 - dio3，证实了先前在另一种小鼠代谢疾病模型中rAAV在dlk1 - dio3位点整合的研究。在一个案例中，整合载体被证实在每个细胞中大约有一个拷贝，与克隆扩增一致。在肝结节/肿瘤组织中，在tax1bp1基因附近也检测到另一个已证实的整合位点，每个细胞约有一个拷贝。dlk1 - dio3区域也与人类HCC有关，因此在正在进行的rAAV载体人体临床试验中需要仔细监测。
Recombinant adeno-associated viruses (rAAVs) have been tested in humans and other large mammals without adverse events. However, one study of mucopolysaccharidosis VII correction in mice showed repeated integration of rAAV in cells from hepatocellular carcinoma (HCC) in theDlk1–Dio3locus, suggesting possible insertional mutagenesis. In contrast, another study found no association of rAAV integration with HCC, raising questions about the generality of associations between liver transformation and integration atDlk1–Dio3. Here we report that in rAAV-treated ornithine transcarbamylase (Otc)–deficient mice, four examples of integration sites inDlk1–Dio3could be detected in specimens from liver nodule/tumors, confirming previous studies of rAAV integration in theDlk1–Dio3locus in the setting of another murine model of metabolic disease. In one case, the integrated vector was verified to be present at about one copy per cell, consistent with clonal expansion. Another verified integration site in liver nodule/tumor tissue near theTax1bp1gene was also detected at about one copy per cell. TheDlk1–Dio3region has also been implicated in human HCC and so warrants careful monitoring in ongoing human clinical trials with rAAV vectors.