Lack of genotoxicity due to foamy virus vector integration in human iPSCs
Authors:
Open Access
- 7 February 2013
- journal article
- research article
- Published by Springer Nature in Gene Therapy
- Vol. 20 (8) , 868-873
Abstract
Integrating vectors can lead to the dysregulation of nearby chromosomal genes, with important consequences for clinical trials and cellular engineering. This includes the retroviral and lentiviral vectors commonly used for deriving induced pluripotent stem cells (iPSCs). We previously used integrating foamy virus (FV) vectors expressing OCT4, SOX2, MYC and KLF4 to reprogram osteogenesis imperfecta mesenchymal stem cells (MSCs). Here, we have studied the effects of 10 FV vector proviruses on neighboring gene expression in four iPSC lines and their corresponding iPSC-derived MSC (iMSCs). Gene expression profiles in these iPSC lines showed that none of the 38 genes within 300 kb up- or downstream of integrated proviruses had a significant difference in mRNA levels, including five genes with proviruses in their transcription units. In the iMSCs derived from these iPSCs, the same type of analysis showed a single dysregulated transcript out of 46 genes found near proviruses. This frequency of dysregulation was similar to that of genes lacking nearby proviruses, so it may have been due to interclonal variation and/or measurement inaccuracies. While the number of integration sites examined in this paper is limited, our results suggest that integrated FV proviruses do not impact the expression of chromosomal genes in pluripotent human stem cells or their differentiated derivatives. This interpretation is consistent with previous reports that FV vectors have minimal genotoxicity, even when integrating near or within genes.Keywords
This publication has 41 references indexed in Scilit:
- Normal Collagen and Bone Production by Gene-targeted Human Osteogenesis Imperfecta iPSCsMolecular Therapy, 2012
- Distribution of Lentiviral Vector Integration Sites in Mice Following Therapeutic Gene Transfer to Treat β-thalassemiaMolecular Therapy, 2011
- Integration profile of retroviral vector in gene therapy treated patients is cell‐specific according to gene expression and chromatin conformation of target cellEMBO Molecular Medicine, 2011
- Lentivirus-mediated Reprogramming of Somatic Cells in the Absence of Transgenic Transcription FactorsMolecular Therapy, 2010
- No Evidence for Clonal Selection Due to Lentiviral Integration Sites in Human Induced Pluripotent Stem CellsStem Cells, 2010
- Genotoxic Potential of Lineage-specific Lentivirus Vectors Carrying the β-Globin Locus Control RegionMolecular Therapy, 2009
- Insertional Transformation of Hematopoietic Cells by Self-inactivating Lentiviral and Gammaretroviral VectorsMolecular Therapy, 2009
- Transcriptional Enhancers Induce Insertional Gene Deregulation Independently From the Vector Type and DesignMolecular Therapy, 2009
- Genomic and Functional Assays Demonstrate Reduced Gammaretroviral Vector Genotoxicity Associated With Use of the cHS4 Chromatin InsulatorMolecular Therapy, 2009
- Patterns of somatic mutation in human cancer genomesNature, 2007