ArticleJournal of virology2006
A helper-dependent capsid-modified adenovirus vector expressing adeno-associated virus rep78 mediates site-specific integration of a 27-kilobase transgene cassette.
Article in Journal of virology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- High-Level rAAV Vector Production by rAdV-Mediated Amplification of Small Amounts of Input Vector.Viruses · 2022Article
- Targeted Integration and High-Level Transgene Expression in AAVS1 Transgenic Mice after In Vivo HSC Transduction with HDAd5/35++ Vectors.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Adenovirus vectors in hematopoietic stem cell genome editing.FEBS letters · 2019Review
- A High-Capacity Adenoviral Hybrid Vector System Utilizing the Hyperactive Sleeping Beauty Transposase SB100X for Enhanced Integration.Molecular therapy. Nucleic acids · 2016Article
- A Regulatory Element Near the 3' End of the Adeno-Associated Virus rep Gene Inhibits Adenovirus Replication in cis by Means of p40 Promoter-Associated Short Transcripts.Journal of virology · 2016Article
- Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation.Molecular therapy. Methods & clinical development · 2015Article
- Differential contribution of adeno-associated virus type 2 Rep protein expression and nucleic acid elements to inhibition of adenoviral replication in cis and in trans.Journal of virology · 2014Article
- Adeno-associated virus type 2 wild-type and vector-mediated genomic integration profiles of human diploid fibroblasts analyzed by third-generation PacBio DNA sequencing.Journal of virology · 2014Article
- Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells.Gene therapy · 2013Article
- Article
- Chimeric piggyBac transposases for genomic targeting in human cells.Nucleic acids research · 2012Article
- Computationally designed adeno-associated virus (AAV) Rep 78 is efficiently maintained within an adenovirus vector.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Chromosomal integration of adenoviral vector DNA in vivo.Journal of virology · 2010Article
- Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome.PLoS pathogens · 2010Article
- Article
- Targeted chromosomal insertion of large DNA into the human genome by a fiber-modified high-capacity adenovirus-based vector system.PloS one · 2008Article
- Barriers for retinal gene therapy: separating fact from fiction.Vision research · 2008Review
- Tightly regulated gene expression in human hematopoietic stem cells after transduction with helper-dependent Ad5/35 vectors.Experimental hematology · 2008Article
- Adeno-associated virus integration: virus versus vector.Gene therapy · 2008Review
- Integration of active human beta-galactosidase gene (100 kb) into genome using HSV/AAV amplicon vector.Gene therapy · 2007Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
Random integration of viral gene therapy vectors and subsequent activation or disruption of cellular genes poses safety risks. Major efforts in the field are aimed toward targeting vector integration to specific sites in the host genome. The adeno-associated virus (AAV) Rep78 protein is able to target AAV integration to a specific site on human chromosome 19, called AAVS1. We studied whether this ability could be harnessed to achieve site-specific integration of a 27-kb transgene cassette into a model cell line for human hematopoietic cells (Mo7e). To deliver rep78 and the transgene to Mo7e cells, we used helper-dependent adenovirus (Ad) vectors containing Ad serotype 35 fiber knob domains (HD-Ad). An HD-Ad vector containing the rep78 gene under the control of the globin locus control region (LCR) (Ad.LCR-rep78) conferred Rep78 expression on Mo7e cells. Upon coinfection of Ad.LCR-rep78 with an HD-Ad vector containing a 27-kb globin-LCR-green fluorescent protein (GFP) transgene cassette flanked by AAV inverted terminal repeats (ITRs) (Ad.AAV-LCR-GFP), transduced cells were cloned and expanded (without selection pressure), and vector integration was analyzed in clones with more than 30% GFP-positive cells. Vector integration into the AAVS1 region was seen in 30% of analyzed integration sites, and GFP expression from these integrants was stable over time. Of the remaining integration sites, 25% were within the genomic globin LCR. In almost 90% of sites, transgene integration occurred via the Ad ITR. This indicates that rescue of the AAV ITR-flanked transgene cassette from Ad.AAV-LCR-GFP is not required for Rep78-mediated integration into AAVS1 and that free ends within the vector genome can be created by breaks within the Ad ITRs, whose structure is apparently recognized by cellular "nicking" enzymes. The finding that 55% of all analyzed integration sites were either within the AAVS1 or globin LCR region demonstrates that a high frequency of targeted integration of a large transgene cassette can be achieved in human hematopoietic stem cell lines.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.