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Directed evolution of adenine base editors with increased activity and therapeutic application

Authors :
Nicole M, Gaudelli
Dieter K, Lam
Holly A, Rees
Noris M, Solá-Esteves
Luis A, Barrera
David A, Born
Aaron, Edwards
Jason M, Gehrke
Seung-Joo, Lee
Alexander J, Liquori
Ryan, Murray
Michael S, Packer
Conrad, Rinaldi
Ian M, Slaymaker
Jonathan, Yen
Lauren E, Young
Giuseppe, Ciaramella
Source :
Nature biotechnology. 38(7)
Publication Year :
2019

Abstract

The foundational adenine base editors (for example, ABE7.10) enable programmable A•T to G•C point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG protospacer adjacent motif (PAM) sites, ABE8s result in ~1.5× higher editing at protospacer positions A5-A7 and ~3.2× higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ~4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34

Details

ISSN :
15461696
Volume :
38
Issue :
7
Database :
OpenAIRE
Journal :
Nature biotechnology
Accession number :
edsair.pmid..........89944f55dcb3a2ec2e0c6f02b02445b3