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Nat Genet. 2017 Aug;49(8):1267-1273. doi: 10.1038/ng.3893. Epub 2017 Jun 19.

Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome.

Author information

1
Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Sydney, New South Wales, Australia.
2
Bioinformatics Unit, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
3
Embryology Unit, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
4
Translational Vectorology Group, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
5
Molecular Immunology Unit, Centre for Immunodeficiency, Institute of Child Health, University College London, London, UK.
6
Department of Medicine, University of Washington, Seattle, Washington, USA.
7
Department of Biochemistry, University of Washington, Seattle, Washington, USA.
8
Military Institute of Hygiene and Epidemiology, Puławy, Poland.
9
Discipline of Child and Adolescent Health, University of Sydney, Westmead, New South Wales, Australia.

Abstract

Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC.

PMID:
28628105
DOI:
10.1038/ng.3893
[Indexed for MEDLINE]

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