Highly efficient multiplex human T cell engineering without double-strand breaks using Cas9 base editors

Beau R. Webber, Cara-lin Lonetree, Mitchell G. Kluesner, Matthew J. Johnson, Emily J. Pomeroy, Miechaleen D. Diers, Walker S. Lahr, Garrett M. Draper, Nicholas J. Slipek, Branden A. Smeester, Klaus N. Lovendahl, Amber N. McElroy, Wendy R. Gordon, Mark J. Osborn and Branden S. Moriarity ()
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Beau R. Webber: University of Minnesota
Cara-lin Lonetree: University of Minnesota
Mitchell G. Kluesner: University of Minnesota
Matthew J. Johnson: University of Minnesota
Emily J. Pomeroy: University of Minnesota
Miechaleen D. Diers: University of Minnesota
Walker S. Lahr: University of Minnesota
Garrett M. Draper: University of Minnesota
Nicholas J. Slipek: University of Minnesota
Branden A. Smeester: University of Minnesota
Klaus N. Lovendahl: University of Minnesota
Amber N. McElroy: University of Minnesota
Wendy R. Gordon: University of Minnesota
Mark J. Osborn: University of Minnesota
Branden S. Moriarity: University of Minnesota

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract The fusion of genome engineering and adoptive cellular therapy holds immense promise for the treatment of genetic disease and cancer. Multiplex genome engineering using targeted nucleases can be used to increase the efficacy and broaden the application of such therapies but carries safety risks associated with unintended genomic alterations and genotoxicity. Here, we apply base editor technology for multiplex gene modification in primary human T cells in support of an allogeneic CAR-T platform and demonstrate that base editor can mediate highly efficient multiplex gene disruption with minimal double-strand break induction. Importantly, multiplex base edited T cells exhibit improved expansion and lack double strand break-induced translocations observed in T cells edited with Cas9 nuclease. Our findings highlight base editor as a powerful platform for genetic modification of therapeutically relevant primary cell types.

Date: 2019
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DOI: 10.1038/s41467-019-13007-6

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