AAV vector integration sites in mouse hepatocellular carcinoma
Abstract
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.
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Gene addition approaches with AAV are limited by increased mutagenic and oncogenic risks.
“and increased mutagenic and oncogenic risks.5”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [5]
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Self-citation
- Authors
- Donsante, A., Miller, D. G., Li, Y., Vogler, C., Brunt, E. M., Russell, D. W., & Sands, M. S.
- Affiliations
- University of Washington (US)
- Corresponding author
- Donsante, Anthony
- Miller, Daniel G.
- Russell, David W.
- Sands, Mark S.
- Venue
- Science
- Published
- 2007-07-27
- Volume
- 317
- Issue
- 5837
- Pages
- 477-477
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2075953769
- Cited by
- 662
- References
- 7
- Citations by year
- 2026: 27 · 2025: 30 · 2024: 37 · 2023: 45 · 2022: 35 · 2021: 35 · 2020: 45 · 2019: 22 · 2018: 25 · 2017: 30 · 2016: 31 · 2015: 40 · 2014: 23 · 2013: 28 · 2012: 39
- FWCI
- 21.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071657)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- adeno-associated virus vectors, hepatocellular carcinoma, mucopolysaccharidosis VII, β-glucuronidase expression, chromosome 12, genomic imprinting, small nucleolar RNA, microRNA, carcinogenesis, gene therapy safety, mouse model
- MeSH terms
- Dependovirus, Animals, Cell Transformation, Viral, Genetic Vectors, Glucuronidase, Carcinoma, Hepatocellular, Liver, Liver Neoplasms, Mice, Transgenic, Proviruses, Mutagenesis, Insertional, Virus Integration, Terminal Repeat Sequences, Oligonucleotide Array Sequence Analysis, RNA, Small Nucleolar, MicroRNAs, Mice
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