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Nat Biotechnol. 2018 Oct;36(9):843-846. doi: 10.1038/nbt.4172. Epub 2018 May 29.

Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction.

Koblan LW1,2,3, Doman JL1,2,3, Wilson C1,2,3, Levy JM1,2,3, Tay T1,2,3, Newby GA1,2,3, Maianti JP1,2,3, Raguram A1,2,3, Liu DR1,2,3.

Author information

1
Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
2
Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA.
3
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Abstract

Base editors enable targeted single-nucleotide conversions in genomic DNA. Here we show that expression levels are a bottleneck in base-editing efficiency. We optimize cytidine (BE4) and adenine (ABE7.10) base editors by modification of nuclear localization signals (NLS) and codon usage, and ancestral reconstruction of the deaminase component. The resulting BE4max, AncBE4max, and ABEmax editors correct pathogenic SNPs with substantially increased efficiency in a variety of mammalian cell types.

PMID:
29813047
PMCID:
PMC6126947
DOI:
10.1038/nbt.4172
[Indexed for MEDLINE]
Free PMC Article

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