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• W2561061844 abstract "Retroviral (RV) vector mediated gene therapy offers immense potential for permanently treating a broad spectrum of genetic conditions and has shown efficacy in clinical trials. However, vector proviruses can dysregulate nearby host genes, referred to as genotoxicity, which can lead to oncogenic transformation. Studies on the integration profiles and the mechanisms responsible for targeting integration have been carried out, resulting in a better understanding of the safety of RV vectors. Integration is influenced by the pre-integration complex (PIC) and its interactions with host proteins. Retargeting RV vectors to safe locations in the genome is an important step in reducing potential genotoxic effects. Although the RV PIC and its interactions are poorly defined, studies have shown that it is possible to retarget RV vector integration. It has been demonstrated that lentiviral vector integration can be retargeted using artificial tethering factors. A modified cell line was produced that expressed lens epithelium–derived growth factor (LEDGF) fused to chromobox protein homolog 1 (CBX1) in place of the wild type LEDGF. The LEDGF-CBX1 fusion protein targeted lentiviral vector integration into methylated regions in the human genome. However, this strategy requires modifying a cell to express a fusion protein and is therefore not practical for clinical use. Other studies have also shown it is possible to retarget RV vector integration, but these studies resulted in reduced transgene expression or impaired vector titers. A clinically relevant method for retargeting integration to safer genomic locations is needed.Here we demonstrate an approach to retarget foamy viral (FV) vector integration into safer heterochromatic regions that does not require a modified cell line. Foamy viruses have a broad tropism, a large packaging capacity, and efficiently transduce hematopoietic stem cells, making them well suited for gene therapy. We describe a FV vector with a modified Pol which expresses an integrase-CBX1 (IN-CBX1) fusion protein and a modified Gag which expresses a mutated chromatin binding site (CBS) domain. CBX1 binds to trimethylated histone H3K9 (H3K9me3), so we hypothesized the IN-CBX1 fusion protein would target FV vector integration into heterochromatin. The integration sites of the modified FV vector (n = 1494) and the control FV vector were compared in normal human fibroblast cells. We analyzed the retargeting ability by comparing the integration sites to normal human fibroblast H3K9me3 ChIP-Seq data. Significant retargeting to H3K9me3 regions was observed with the modified FV vector (P 107 transducing units/ml). This study demonstrates that FV vectors can be efficiently retargeted using foamy integrase fusion proteins. Since this approach does not require engineering the target cells, it is promising for use in the clinic, including hematopoietic stem cell gene therapy." @default.
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• W2561061844 date "2015-05-01" @default.
• W2561061844 modified "2023-09-23" @default.
• W2561061844 title "533. A Clinically Relevant Approach for Retargeting Foamy Viral Vectors Into Heterochromatin" @default.
• W2561061844 doi "https://doi.org/10.1016/s1525-0016(16)34142-9" @default.
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