Adenine transversion editors enable precise, efficient A•T-to-C•G base editing in mammalian cells and embryos
Chen et al. (2024) introduce adenine-to-cytosine base editors (ACBEs) — fusion proteins combining mouse alkyladenine DNA glycosylase (mAAG) with nickase Cas9 and TadA-8e deaminase. Laboratory evolution of mAAG increased A→C/T conversion efficiency from baseline to 73% maximum, yielding precise A•T→C•G transversions with minimal Cas9-independent off-targeting. In mouse embryos, founder mice showed 44–56% average A→C edits with allelic frequencies reaching 100%.
Relevance to h07 (Misha’s STRC mutation): ACBE goes the WRONG direction for Misha’s c.4976A>C variant. Misha has a C on the coding strand at the mutant position; correction requires C→A (not A→C). ACBE would CREATE the mutation, not fix it. ACBE is relevant only for other DFNB16 patients with different variant classes, or as a size-advantage reference (ACBE is ~130 kDa vs PE3 ~180 kDa; single-AAV compatible).
Author note: This paper was cited in h07 notes as “Kim 2023.” PMID 37322276 belongs to Chen L et al. (2024, Nature Biotechnology), not Kim. There is no author named Kim in the author list. Published 2024 (epub June 2023 — explaining the “2023” year confusion). First author is Liang Chen (Dali Li lab + Liu lab collaboration).
Key finding
A→C transversion editors reach 73% (evolved) in cell culture, 44–56% in embryos. Smaller payload than PE3 favors single-AAV packaging. But the edit direction is A→C, which creates Misha’s STRC mutation (c.4976A>C) rather than correcting it.
Numbers that matter
| Parameter | Value | Units | Source | Conditions |
|---|---|---|---|---|
| Max ACBE efficiency (evolved mAAG) | 73 | % | Abstract | Cell culture, evolved variant, A→C conversion |
| Founder mouse embryo efficiency | 44–56 | % (average) | Abstract | Mouse embryos, A→C edits |
| Embryo allelic frequency (max) | 100 | % | Abstract | Best-case allele |
| ACBE size | ~130 | kDa | Paper | Enables single-AAV delivery (vs PE3 ~180 kDa) |
| PE3 size | ~180 | kDa | Literature | Requires dual-AAV |
| Edit type | A•T → C•G | transversion | Abstract | Cannot perform C→A correction |
Limitations
- Wrong edit direction for Misha’s STRC c.4976A>C variant: correcting C→A on coding strand requires prime editing, not ACBE.
- No in vivo post-mitotic data in neuronal or cochlear cells reported.
- Embryo data; somatic adult tissue efficiencies not shown in abstract.
- Off-target profile in vivo not characterized in abstract.
Connections
[source]Prime Editing for STRC — ACBE context for h07; single-AAV size advantage; wrong direction for Misha[part-of]prime-editing — prime-editing topic parameter table[applies]h07 hub — rules out ACBE for Misha’s specific variant; relevant for other DFNB16 patients[see-also]2019-anzalone-prime-editing-nature — PE3 is required for Misha’s C→A correction