Stephen, Sam Laurel, Montini, Eugenio ORCID: 0000-0003-1771-6067, Sivanandam, Vijayshankar Ganesh, Al-Dhalimy, Muhseen, Kestler, Hans A. ORCID: 0000-0002-4759-5254, Finegold, Milton, Grompe, Markus ORCID: 0000-0002-6616-4345 and Kochanek, Stefan (2010). Chromosomal Integration of Adenoviral Vector DNA In Vivo. J. Virol., 84 (19). S. 9987 - 9995. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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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 FAH(Delta exon5) 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 x 10(-5) per transduced hepatocyte, while homologous recombination occurred more rarely with a median frequency of 3.88 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stephen, Sam LaurelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montini, EugenioUNSPECIFIEDorcid.org/0000-0003-1771-6067UNSPECIFIED
Sivanandam, Vijayshankar GaneshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Dhalimy, MuhseenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kestler, Hans A.UNSPECIFIEDorcid.org/0000-0002-4759-5254UNSPECIFIED
Finegold, MiltonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grompe, MarkusUNSPECIFIEDorcid.org/0000-0002-6616-4345UNSPECIFIED
Kochanek, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-495924
DOI: 10.1128/JVI.00751-10
Journal or Publication Title: J. Virol.
Volume: 84
Number: 19
Page Range: S. 9987 - 9995
Date: 2010
Publisher: AMER SOC MICROBIOLOGY
Place of Publication: WASHINGTON
ISSN: 1098-5514
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TYROSINEMIA TYPE-I; TRANSCRIPTION START REGIONS; EMBRYONIC STEM-CELLS; DE-NOVO METHYLATION; GENE-THERAPY; HUMAN GENOME; SPONTANEOUS MUTATION; CELLULAR DNA; FOAMY VIRUS; VIRAL-DNAMultiple languages
VirologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/49592

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