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Science 27 July 2007:
Vol. 317. no. 5837, p. 477
DOI: 10.1126/science.1142658
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AAV Vector Integration Sites in Mouse Hepatocellular Carcinoma

Anthony Donsante,1* Daniel G. Miller,2* Yi Li,3,4 Carole Vogler,5 Elizabeth M. Brunt,5 David W. Russell,3,4{dagger} Mark S. Sands1,6{dagger}

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.

1 Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
2 Department of Pediatrics, University of Washington, Seattle, WA 98112, USA.
3 Department of Medicine, University of Washington, Mail Stop 357720, Seattle, WA 98112, USA.
4 Department of Biochemistry, University of Washington, Seattle, WA 98112, USA.
5 Department of Pediatrics, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
6 Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.

* These authors contributed equally to this study.

{dagger} To whom correspondence should be addressed. E-mail: msands{at}im.wustl.edu (M.S.S.); drussell{at}u.washington.edu (D.W.R.)

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Science. ISSN 0036-8075 (print), 1095-9203 (online)