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Browning DL
; Collins CP
; Hocum JD
; Leap DJ
; Rae DT
; Trobridge GD
Hum Gene Ther
2016[Mar]; 27
(3
): 255-66
PMID26715244
show ga
Retroviral vector-mediated gene therapy is promising, but genotoxicity has
limited its use in the clinic. Genotoxicity is highly dependent on the retroviral
vector used, and foamy viral (FV) vectors appear relatively safe. However,
internal promoters may still potentially activate nearby genes. We developed
insulated FV vectors, using four previously described insulators: a version of
the well-studied chicken hypersensitivity site 4 insulator (650cHS4), two
synthetic CCCTC-binding factor (CTCF)-based insulators, and an insulator based on
the CCAAT box-binding transcription factor/nuclear factor I (7xCTF/NF1). We
directly compared these insulators for enhancer-blocking activity, effect on FV
vector titer, and fidelity of transfer to both proviral long terminal repeats.
The synthetic CTCF-based insulators had the strongest insulating activity, but
reduced titers significantly. The 7xCTF/NF1 insulator did not reduce titers but
had weak insulating activity. The 650cHS4-insulated FV vector was identified as
the overall most promising vector. Uninsulated and 650cHS4-insulated FV vectors
were both significantly less genotoxic than gammaretroviral vectors. Integration
sites were evaluated in cord blood CD34(+) cells and the 650cHS4-insulated FV
vector had fewer hotspots compared with an uninsulated FV vector. These data
suggest that insulated FV vectors are promising for hematopoietic stem cell gene
therapy.
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