AAV vector integration sites in mouse hepatocellular carcinoma.
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.
Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Anthony
A
Donsante
Daniel G
DG
Miller
Yi
Y
Li
Carole
C
Vogler
Elizabeth M
EM
Brunt
David W
DW
Russell
Mark S
MS
Sands
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D002472:Cell Transformation, Viral; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors; D005966:Glucuronidase / Q000235:genetics; D008099:Liver / Q000821:virology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D016254:Mutagenesis, Insertional; D020411:Oligonucleotide Array Sequence Analysis; D011533:Proviruses / Q000235:genetics; D020537:RNA, Small Nucleolar / Q000235:genetics; D020079:Terminal Repeat Sequences; D016662:Virus Integration
D035683:MicroRNAs; D020537:RNA, Small Nucleolar; D005966:Glucuronidase