Engineering a precise adenine base editor with minimal bystander editing

ABE9 shows 342.5-fold precision in editing compared to ABE8e.

• Adenine base editors (ABEs) can facilitate A-to-G transitions but raise safety concerns due to bystander mutations and off-target effects.
• The N108Q mutation in ABE8e reduced bystander editing of adenine and cytosine, while the additional L145T mutation in ABE9 further refined the editing window to 1-2 nucleotides.
• ABE9 displayed very minimal RNA and undetectable DNA off-target effects, primarily achieving the desired single A-to-G conversion in mouse and rat embryos.
• ABE9 accurately edited the A-position of pathogenic homopolymeric adenosine sequences, significantly improving precision over its predecessor.
• The minimized editing window of ABE9 could enhance the targeting scope for correcting pathogenic single-nucleotide variants when combined with compatible Cas9 variants.

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