A precise and efficient adenine base editor

Jul 13, 2022Molecular therapy : the journal of the American Society of Gene Therapy

A highly accurate and efficient tool for editing DNA base adenine

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Abstract

NG-ABE9e exhibits more than 7-fold reduction in bystander editing compared to NG-ABE8e in human cells.

NG-ABE9e is a novel adenine base editor variant with nine mutations.
It shows robust and precise base-editing activity in human cells.
Bystander editing is reduced by approximately 4-fold when correcting the T17M mutation in Rhodopsin.
NG-ABE9e has substantially higher editing activity than NG-ABEmax.
In rice, NG-ABE9e demonstrates significantly lower bystander editing compared to NG-ABE8e.

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Adenine base editors (ABEs) are novel genome-editing tools, and their activity has been greatly enhanced by eight additional mutations, thus named ABE8e. However, elevated catalytic activity was concomitant with frequent generation of bystander mutations. This bystander effect precludes its safe applications required in human gene therapy. To develop next-generation ABEs that are both catalytically efficient and positionally precise, we performed combinatorial engineering of NG-ABE8e. We identify a novel variant (NG-ABE9e), which harbors nine mutations. NG-ABE9e exhibits robust and precise base-editing activity in human cells, with more than 7-fold bystander editing reduction at some sites, compared with NG-ABE8e. To demonstrate its practical utility, we used NG-ABE9e to correct the frequent T17M mutation in Rhodopsin for autosomal dominant retinitis pigmentosa. It reduces bystander editing by ∼4-fold while maintaining comparable efficiency. NG-ABE9e possesses substantially higher activity than NG-ABEmax and significantly lower bystander editing than NG-ABE8e in rice. Therefore, this study provides a versatile and improved adenine base editor for genome editing.

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A precise and efficient adenine base editor

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