Donsante Anthony, Miller Daniel G, Li Yi, Vogler Carole, Brunt Elizabeth M, Russell David W, Sands Mark S
Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Science. 2007 Jul 27;317(5837):477. doi: 10.1126/science.1142658.
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.
腺相关病毒（AAV）是很有前景的基因治疗载体，几乎没有急性毒性或完全没有急性毒性。我们发现，正常小鼠和患有黏多糖贮积症VII型（MPS VII）的小鼠在新生期注射表达β-葡萄糖醛酸酶的AAV载体后会发生肝细胞癌（HCC）。从四个肿瘤中分离出AAV前病毒，它们都位于12号染色体的一个6千碱基区域内。该位点编码几种印记转录本、小核仁RNA（snoRNA）和微小RNA。编码snoRNA和微小RNA的相邻基因的转录本在肿瘤中过度表达。我们的研究结果表明该位点与HCC的发生有关，并引发了对AAV载体临床应用的担忧。
