Optimized in vivo base editing restores auditory function in a DFNA15 mouse model
Wang et al. (2025) demonstrate full therapeutic chain in a cochlear gene editing model: SchABE8e (a next-generation adenine base editor) delivered via Anc80L65 synthetic AAV to neonatal mice corrects the Pou4f3-Q113* nonsense mutation causing DFNA15 (dominant non-syndromic deafness). In vitro SchABE8e achieved 48.5% editing of the Q113* codon. Neonatal cochlear injection produced near-complete hearing recovery sustained for at least four months. Biosafety analyses were favorable.
Author note: This paper was cited as “Zhang 2025” in prior h07 notes. The first author is Man Wang; Ziyu Zhang is a co-author (explaining the misattribution). PMID 40968144 is confirmed correct for Wang et al. 2025 Nature Communications. Corrected 2026-04-25.
Key finding
Anc80L65 + SchABE8e corrects a cochlear stop mutation in vivo with near-complete functional rescue at 4+ months. This is the closest published proof-of-concept for the h07 delivery chain (AAV → OHCs → precision base correction → sustained hearing recovery), despite using ABE (A→G) rather than PE. It validates the entire pipeline except the edit chemistry.
Numbers that matter
| Parameter | Value | Units | Source | Conditions |
|---|---|---|---|---|
| SchABE8e in vitro editing efficiency | 48.5 | % | Abstract | Cell culture, Pou4f3-Q113* locus |
| Functional hearing recovery | Near-complete | — | Abstract | Neonatal mouse, Anc80L65 injection |
| Recovery persistence | ≥4 | months | Abstract | Sustained follow-up |
| AAV vector | Anc80L65 | — | Abstract | Preferred for OHC cochlear delivery |
| Target gene | Pou4f3 (POU4F3) | — | Abstract | Q113* nonsense mutation; DFNA15 |
| Edit type | A→G (ABE); A•T→G•C | — | Abstract | Cannot correct C→A as needed for Misha |
Limitations
- ABE edits A→G; Misha’s STRC variant requires C→A correction on coding strand — different edit chemistry. This paper validates the delivery and functional rescue but not the PE edit type.
- Neonatal injection; efficacy in older animals (Misha’s age ~5 years) likely lower due to OHC maturation and reduced AAV access.
- POU4F3 gene therapy (dominant): one allele correction sufficient. Misha’s DFNB16 is recessive; both alleles need consideration.
- DFNA15 model (dominant): loss of POU4F3 transcription factor. DFNB16 (STRC loss-of-function) is different pathobiology.
Connections
[source]Prime Editing for STRC — Anc80L65 + ABE OHC delivery and functional rescue chain; corrected from “Zhang 2025”[source]STRC Cross-Hypothesis Verification Sweep 2026-04-25 — first-author corrected this turn[part-of]prime-editing — prime-editing topic parameter table[applies]h07 hub — validates AAV→OHC→edit→rescue pipeline; ABE not PE, but delivery proof direct[see-also]2021-shubina-oleinik-strc-dual-aav-dfnb16 — DFNB16-specific (STRC) cochlear dual-AAV therapy