Efficient prime editing in mouse brain, liver and heart with dual AAVs
Davis et al. (2024) engineered dual-AAV split-intein prime editor systems (v1em and v3em PE-AAV) that overcome AAV cargo limits (~4.7 kb) by splitting the PE3 construct across two viral particles with intein-mediated reassembly. In adult mice, these systems achieved post-mitotic editing efficiencies that substantially exceed prior PE benchmarks: up to 42% in cortex, 46% in liver, 11% in heart. Safety profiling showed no detectable off-target edits and no significant liver enzyme changes, establishing a therapeutic-grade delivery architecture directly applicable to h07.
Key finding
Dual-AAV split PE can edit post-mitotic cortical neurons at 42% unenriched efficiency in vivo — the highest reported as of 2024. Protective mutations for Alzheimer’s (brain) and coronary artery disease (liver) were introduced as proof of therapeutic utility. The v3em variant outperformed v1em in most tissues.
Numbers that matter
| Parameter | Value | Units | Source | Conditions |
|---|---|---|---|---|
| Cortical neuron editing efficiency | 42 | % | Abstract / Fig 3 | Adult mouse, dual-AAV8, v3em PE-AAV, unenriched |
| Liver editing efficiency | 46 | % | Abstract / Fig 4 | Adult mouse, dual-AAV8, v3em PE-AAV, unenriched |
| Heart editing efficiency | 11 | % | Abstract / Fig 4 | Adult mouse, dual-AAV8, v3em PE-AAV, unenriched |
| Off-target edits detected | 0 | count | Abstract | Whole-genome sequencing |
| PE payload size (unfragmented) | ~6.3 | kb | known PE3 architecture | Too large for single AAV |
| AAV packaging limit | ~4.7 | kb | known | Standard rAAV |
Limitations
- Adult mouse cortex ≠ OHCs: OHCs are more terminally differentiated and have distinct AAV transduction kinetics. Cochlear data absent.
- Efficiency varies dramatically by tissue (11% heart vs 42% cortex), suggesting cell-type-specific barriers matter.
- v3em vs v1em head-to-head only in specific tissues; best variant for cochlea is unknown.
- No long-term persistence data beyond the acute experiment window reported in abstract.
Connections
[source]Prime Editing for STRC — 42% cortical neuron efficiency; best post-mitotic in vivo PE benchmark for h07 OHC extrapolation[source]STRC Cross-Hypothesis Verification Sweep 2026-04-25 — first-author corrected from “Chen 2024” → Davis/Banskota 2024[part-of]prime-editing — prime-editing topic parameter table[applies]h07 hub — primary efficiency anchor for OHC prime editing feasibility claim[see-also]2019-anzalone-prime-editing-nature — original PE paper by same Liu lab