AAV vector integration sites in mouse hepatocellular carcinoma
AAV vector integration sites in mouse hepatocellular carcinoma
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DOI：
10.1126/science.1142658
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发表时间：
2007-07-27
期刊：
影响因子：
56.9
通讯作者：
Sands, Mark S.
中科院分区：
文献类型：
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作者：
Donsante, Anthony;Miller, Daniel G.;Sands, Mark S.
腺相关病毒（Adeno-associated viruses，AAV）是一种有前途的基因治疗载体，具有很小或没有急性毒性。我们发现，正常小鼠和粘多糖沉积症VII（MPS VII）小鼠在新生儿注射表达β-葡萄糖醛酸苷酶的AAV载体后发生肝细胞癌（HCC）。从四个肿瘤中分离出了腺相关病毒前病毒，它们都位于12号染色体的6千碱基区域内。该基因座编码几种印迹转录物、小核仁RNA（snoRNA）和microRNA。来自编码snoRNA和microRNA的相邻基因的转录物在肿瘤中过表达。我们的研究结果暗示这个位点在HCC的发展中，并引起了对AAV载体临床应用的关注。
Adeno-associated viruses (AAV) are promising gene therapy vectors that have little or no acute toxicity. We show that normal mice and mice with mucopolysaccharidosis VII (MPS VII) develop hepatocellular carcinoma (HCC) after neonatal injection of an AAV vector expressing b-glucuronidase. AAV proviruses were isolated from four tumors and were all located within a 6-kilobase region of chromosome 12. This locus encodes several imprinted transcripts, small nucleolar RNAs (snoRNAs), and microRNAs. Transcripts from adjacent genes encoding snoRNAs and microRNAs were overexpressed in tumors. Our findings implicate this locus in the development of HCC and raise concerns over the clinical use of AAV vectors.