Nature communicationsDec 18, 2025

Anti-CRISPR Protein AcrIIA5 May Improve the Efficiency and Safety of Prime Editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

AcrIIA5 unexpectedly improved efficiency while reducing byproduct indels in tested genome-editing settings.

Evidence

Cell-based prime editing experiments showed up to 8.2-fold higher activity across PE2, PE3, PE4, PE5, PE6, multiple edit types, and endogenous loci, with fewer indels.

Caveat

The abstract describes mechanistic and locus-spanning editing tests, but not therapeutic delivery, organism-level editing, or long-term safety.

Simplified

(PE) enables the precise installation of intended base substitutions, small deletions or small insertions into the genome of living cells. While the use of Cas9 nickase can avoid DNA double-strand breaks (DSB), undesired insertions and deletions (indels) often accompany the correct edits, particularly when PE activity increased. Here we show that the (Acr) protein AcrIIA5 can significantly enhance PE activity by up to 8.2-fold while markedly reducing byproduct indels. Further investigation reveals that AcrIIA5 can promote PE across various approaches (PE2, PE3, PE4, PE5, and PE6), edit types (substitutions, insertions and deletions), and endogenous loci. Mechanistically, AcrIIA5 appears to inhibit the re-nicking activity of PE complex rather than enhancing the core editing machinery itself, suggesting a distinct mode of interaction with Cas9. Overall, we demonstrate that a known "inhibitor" Acr protein can unexpectedly acting as an "enhancer" of CRISPR/Cas-based genome editing, providing an effective strategy to optimize PE specificity and activity.

Key numbers

8.2×

Increase in Efficiency

enhances activity for base substitutions.

4.5×

Reduction in

reduces undesired in systems.

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Anti-CRISPR Protein AcrIIA5 May Improve the Efficiency and Safety of Prime Editing

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