Base editing of PRNP (split dual-AAV)

Key facts

• Dual-AAV PHP.eB delivering BE3.9max and a guide RNA installing PRNP R37X gave 37 percent average editing, 50 percent lower brain PrP and 52 percent longer lifespan in transgenic human PRNP mice inoculated with pathogenic human prion isolates representing common sporadic and genetic subtypes.
• The Broad calls it the first demonstration that lowering PrP improves lifespan in animals infected with a human version of the protein; the work appeared in Nature Medicine on 14 January 2025.
• R37X was chosen because it occurs naturally in population databases (gnomAD) and lowers protein without apparent harm in people; David Liu approached the team in 2018 and the collaboration followed.
• Funding came from the NIH, the Broad Chemical Biology and Therapeutics Science program, Prion Alliance and HHMI; Liu is senior author.
• The authors present base editing as a potential one-time treatment; the split dual-AAV system needs a high vector dose, so the team has been testing smaller Cas proteins and adenine base editors and says single-AAV strategies are showing success (ASGCT 2026).
• In a 2026 conference account of the split base editor approach, the speaker gave 20 percent editing and 31 percent PrP reduction in humanized PrP mice; the Nature Medicine abstract gives 37 percent editing and 50 percent PrP reduction for the same BE3.9max R37X system, and the sources read do not say why the figures differ.
• Related Broad programs use the same mouse models: the CHARM epigenetic editor (Science 2024) and zinc finger repressors with Sangamo (now owned by Lilly).

Timeline

1. 2018David Liu proposes a collaboration to Minikel and Vallabh.
2. 2025Nature Medicine paper online.
3. 2025Harvard Gazette profile of the work.
4. 2026Jessie Davis presents single-AAV progress at the ASGCT annual meeting.