Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection

Gene Therapy
M E OlszkoG D Trobridge

Abstract

Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34(+) human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rγ(null) mice, and selected in vivo for gene-modified cells. The retroviral insertion site profile of repopulating clones was examined using modified genomic sequencing PCR. We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus promoter known to be genotoxic. Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy but also suggests additional safety features should be developed and evaluated.

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Citations

Dec 31, 2015·Human Gene Therapy·Diana L BrowningGrant D Trobridge
Sep 1, 2016·Molecular Therapy. Methods & Clinical Development·Elizabeth M EversonGrant D Trobridge
Dec 27, 2016·Gene Therapy·D L BrowningG D Trobridge
Mar 28, 2017·Molecular Therapy. Methods & Clinical Development·Charles C BerryFrederic D Bushman
Jun 24, 2018·The Journal of Gene Medicine·Elizabeth M EversonGrant D Trobridge
Mar 29, 2016·Biomedicines·Arun K Nalla, Grant D Trobridge

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