Chromosomal integration of adenoviral vector DNA in vivo

Sam Laurel Stephen, Eugenio Montini, Vijayshankar Ganesh Sivanandam, Muhseen Al-Dhalimy, Hans A. Kestler, Milton Finegold, Markus Grompe, Stefan Kochanek

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44 Scopus citations

Abstract

So far there has been no report of any clinical or preclinical evidence for chromosomal vector integration following adenovirus (Ad) vector-mediated gene transfer in vivo. We used liver gene transfer with high-capacity Ad vectors in the FAHΔexon5 mouse model to analyze homologous and heterologous recombination events between vector and chromosomal DNA. Intravenous injection of Ad vectors either expressing a fumarylacetoacetate hydrolase (FAH) cDNA or carrying part of the FAH genomic locus resulted in liver nodules of FAH-expressing hepatocytes, demonstrating chromosomal vector integration. Analysis of junctions between vector and chromosomal DNA following heterologous recombination indicated integration of the vector genome through its termini. Heterologous recombination occurred with a median frequency of 6.72 × 10-5 per transduced hepatocyte, while homologous recombination occurred more rarely with a median frequency of 3.88 × 10-7. This study has established quantitative and qualitative data on recombination of adenoviral vector DNA with genomic DNA in vivo, contributing to a risk-benefit assessment of the biosafety of Ad vector-mediated gene transfer.

Original languageEnglish (US)
Pages (from-to)9987-9994
Number of pages8
JournalJournal of virology
Volume84
Issue number19
DOIs
StatePublished - Oct 2010

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Stephen, S. L., Montini, E., Sivanandam, V. G., Al-Dhalimy, M., Kestler, H. A., Finegold, M., Grompe, M., & Kochanek, S. (2010). Chromosomal integration of adenoviral vector DNA in vivo. Journal of virology, 84(19), 9987-9994. https://doi.org/10.1128/JVI.00751-10