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Nat Biotechnol. 2018 Oct;36(9):888-893. doi: 10.1038/nbt.4194. Epub 2018 Jul 3.

Optimized base editors enable efficient editing in cells, organoids and mice.

Author information

1
Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
2
Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD program, New York, New York, USA.
3
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York, USA.
4
Helmholtz-University Group 'Cell Plasticity and Epigenetic Remodeling', German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital, Heidelberg, Germany.
5
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, New York, USA.
7
Cold Spring Harbor Laboratory, New York, New York, USA.
8
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
9
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Department of Biochemistry, Weill Cornell Medicine, New York, New York, USA.

Abstract

CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created. The reengineered base editors enable target modification in a wide range of mouse and human cell lines, and intestinal organoids. We also show that the optimized base editors mediate efficient in vivo somatic editing in the liver in adult mice.

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