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• W1987691806 abstract "A drawback of gammaretroviral vectors currently in clinical trials is the risk of insertional activation of neighboring oncogenes by enhancer-promoter elements located in the U3 region of the long terminal repeats (LTRs). Deletion of these elements or incorporation of sequences with enhancer-promoter blocking activity (e.g., chromosomal insulators or polyadenylation sequences) may increase the safety of gammaretroviral-mediated gene delivery in the clinical setting. Here we report the development of two prototypic vectors |[ndash]| MSGV1-C2 and MSinSB |[ndash]| from MSGV1, a derivative of the MSCV backbone exhibiting high level transgene expression due to efficient splicing and translation of vector transcripts. MSGV1-C2 was generated by inserting two copies of the 250-bp |[ldquo]|core|[rdquo]| element from the chicken |[beta]|-globin 5|[prime]|HS4 insulator (Recillas-Targa et al. PNAS 99:6883, 2002) into the U3 region of the 3|[prime]| LTR of MSGV1. MSinSB is a self-inactivating vector in which enhancer-promoter sequences have been deleted from the U3 region of the MSGV1 3|[prime]| LTR (Hawley et al., PNAS 84:2406, 1987) and an internal CAG promoter has been provided to drive transgene transcription. The CAG promoter contains a splice donor that pairs with the env splice acceptor to create an intron in the transgene transcriptional unit when the vector is integrated into the genome of target cells. MSinSB is a variant of the R-region double-copy vector design described by Miller and colleagues (Adam et al., Hum. Gene Ther. 6:1169, 1995). The salient feature of the MSinSB vector plasmid is that it contains two polyadenylation signals in the R region of the 3|[prime]| LTR |[ndash]| the natural retroviral polyadenylation signal and the strong SV40 late region polyadenylation signal |[ndash]| plus a third polyadenylation signal downstream of the U5 region provided by the bovine growth hormone gene. Inclusion of these signals resulted in a 9-fold increase in vector titer compared with the signal-minus version. Using the enhanced green fluorescent protein (GFP) gene as a reporter, MSGV1-C2 and MSinSB titers on mouse NIH3T3 fibroblasts are 1.8 and 0.9 |[times]| 106 transducing units per ml, respectively. In terms of transgene expression, MSinSB consistently directed 3|[ndash]|5-fold higher levels than MSGV1-C2 and the parental MSGV1 vector in NIH3T3 cells, F9 embryonal carcinoma cells and CCE embryonic stem (ES) cells. When transduced CCE ES cells were differentiated into embryoid bodies and hematopoietic cells, the MSinSB vector was observed to be the most resistant to transcriptional extinction with 90 |[plusmn]| 7% hematopoietic cells continuing to express GFP. The two copies of the 5|[prime]|HS4 insulator core element were also found to provide substantial protection against transgene silencing as 20 |[plusmn]| 18% MSGV1-C2-transduced hematopoietic cells continued to express GFP compared with 10 |[plusmn]| 9% of MSGV1-transduced hematopoietic cells. Further characterization of the MSinSB and MSGV1-C2 vectors and assessment of their performance in murine and human hematopoietic stem cell studies are underway, and the results obtained will be presented." @default.
• W1987691806 created "2016-06-24" @default.
• W1987691806 date "2005-05-01" @default.
• W1987691806 modified "2023-10-18" @default.
• W1987691806 title "89. Amelioration of Gamma Retroviral Silencing during Embryonic Stem Cell-Derived Hematopoiesis: Preclinical Assessment of Safety-Improved Vectors" @default.
• W1987691806 doi "https://doi.org/10.1016/j.ymthe.2005.06.067" @default.
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