ArticleGene therapy2008
Site-specific, Rep-mediated integration of the intact beta-globin locus in the human erythroleukaemic cell line K562.
Article in Gene therapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- AAV Infection: Protection from Cancer.Human gene therapy · 2017Article
- Gene Addition Strategies for β-Thalassemia and Sickle Cell Anemia.Advances in experimental medicine and biology · 2017Review
- GFP to BFP Conversion: A Versatile Assay for the Quantification of CRISPR/Cas9-mediated Genome Editing.Molecular therapy. Nucleic acids · 2016Article
- Reply to "Wild-type AAV Insertions in Hepatocellular Carcinoma Do Not Inform Debate Over Genotoxicity Risk of Vectorized AAV".Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Long-term and efficient expression of human β-globin gene in a hematopoietic cell line using a new site-specific integrating non-viral system.Gene therapy · 2015Article
- The therapeutic potential of genome editing for β-thalassemia.F1000Research · 2015Review
- 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
- Nuclease-mediated gene editing by homologous recombination of the human globin locus.Nucleic acids research · 2014Article
- Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells.Gene therapy · 2013Article
- Generation of a genomic reporter assay system for analysis of γ- and β-globin gene regulation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2012Article
- Mouse models for methylmalonic aciduria.PloS one · 2012Article
- Efficient recombinase-mediated cassette exchange at the AAVS1 locus in human embryonic stem cells using baculoviral vectors.Nucleic acids research · 2011Article
- Integration preferences of wildtype AAV-2 for consensus rep-binding sites at numerous loci in the human genome.PLoS pathogens · 2010Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The stable, regulated and tissue-specific expression of a therapeutic transgene can be best achieved by the transfer of a complete genomic locus, which will include the short- and long-range regulatory elements that are critical for the accurate control of gene expression. However, when techniques that rely on the random integration of exogenous DNA into the human genome are used for gene transfer, the risk of insertional mutagenesis remains a major issue. Using components derived from the adeno-associated virus (AAV), we have successfully targeted the integration of 200 kb bacterial artificial chromosomes containing the entire beta-globin locus into the AAVS1 site on human chromosome 19. We show that transient expression of the AAV Rep proteins in K562 cells facilitated site-specific transgene integration in 17% (6 of 36) of all analysed integration sites. Southern blot analysis revealed the locus had integrated into AAVS1 as an intact, functional unit in five of the six clones generated. Furthermore, each of the site-specific integrants exhibited sustained and appropriately regulated transgene gene expression over a period of 8 months of continuous culture in the absence of selective pressure. We anticipate that the approach developed in this study may be suitable for facilitating targeted integration of intact genomic loci in adult and embryonic stem cells, and therefore provide a powerful tool not just for functional studies but in establishing model systems for the ex vivo correction of genetic disorders.
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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.