Prime Editing Therapy — Gene Therapy & Genetic Interventions
Next-generation precision gene editing enabling all 12 possible point mutations plus small insertions and deletions without double-strand breaks.
Overview
Prime editing, developed by David Liu's lab at the Broad Institute (2019), uses a catalytically impaired Cas9 nickase fused to a reverse transcriptase (PE2/PE3) guided by a prime editing guide RNA (pegRNA). It can install any of the 12 possible point mutations, small insertions (up to 44 bp), and small deletions without requiring double-strand breaks or donor DNA templates. Prime Medicine is developing clinical programs for genetic diseases. Prime editing offers lower off-target rates than traditional CRISPR-Cas9 and broader editing capabilities than base editors.
Indications
- Monogenic genetic diseases (sickle cell disease, cystic fibrosis, etc.)
- Correction of pathogenic point mutations
- Insertion of protective genetic variants
- Gene correction in inherited metabolic disorders
- Potential longevity applications (protective variant installation)
Mechanism of Action
Cas9 nickase nicks the non-edited strand at the target site, guided by the spacer sequence of the pegRNA
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Prime Editor (PE2/PE3 + pegRNA) | Study-specific | Single treatment | LNP or dual-AAV delivery |
Evidence Grade
GRADE C
Safety & Contraindications
- Lower off-target editing than Cas9 nuclease but not zero
- Editing efficiency varies by target site, cell type, and pegRNA design
- Large size of prime editor construct limits AAV packaging; dual-AAV or LNP delivery required
- Incomplete editing may result in mosaicism
- Prime Medicine Phase 1 trials initiated for select indications
- Long-term effects of prime editing in vivo require characterization