Nucleic acids researchMar 30, 2026

Controlled system for turning off and switching modes of base editors using sddi

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

Updated Jun 27, 2026

Abstract

Essence

is a small-molecule-switchable base-editing platform that can toggle cytosine and adenine editing on one Cas9 scaffold.

Evidence

This platform engineering and cell-screening study identified inhibitors, achieved up to 43.4% C-to-T and 42.9% A-to-G editing at four endogenous human sites, and used a 4000-member sgRNA screen in MARC-145 cells to find four monkey CD163 amino acids tied to >100-fold lower PRRSV replication.

Caveat

The results are cell-based platform and screening data, so therapeutic versatility and extension to other base editors remain proposed rather than clinically shown.

Simplified

Orthogonal and externally controllable base editors are critical for safe multiplexed single-nucleotide manipulation in vivo. Here, we identify ~140-aa miniature deaminase inhibitors () that bind cognate single-stranded DNA deaminases (Sdds) with high affinity and specificity, occluding their DNA-binding surfaces to completely inhibit C-to-T activity. Based on these inhibitors, we engineer an adenine and cytosine base editing-regulated transformation system (). This platform features two inactive dSdds fused to nCas9 as docking arms, with effector modules provided by doxycycline-inducible SviSddi-SflSdd (CBE) and cumate-inducible Air1Sddi-ABE8e (ABE) fusions. Small-molecule regulation enables switching among four modes (OFF, CBE, ABE, ACBE), achieving up to 43.4% C-to-T or 42.9% A-to-G editing at four endogenous human sites. Using a 4000-member sgRNA library in MARC-145 cells stably expressing ACBE-RTS, a three-round screening identified four key amino acids in monkey CD163 that reduced replication of highly pathogenic PRRSV by >100-fold and eliminated detectable viral-antigen staining. Compact and multi-mode switchable on a single Cas9 scaffold, ACBE-RTS establishes a versatile framework for precision therapeutics and genetic interrogation. Its modular Sddi-Sdd interface could in principle be readily extended to other base editors, such as thymine and guanine base editors (TBE and GBE).

Key numbers

43.4%

C-to-T Editing Efficiency

Achieved at four endogenous human sites in HEK293T cells.

42.9%

A-to-G Editing Efficiency

Achieved in the same experimental setup as C-to-T editing.

>100-fold

Replication Reduction

Reduction in PRRSV replication in monkey CD163 mutants.

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Controlled system for turning off and switching modes of base editors using sddi

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