Nature biomedical engineeringJan 28, 2026

Highly efficient cytosine base editors for precise modeling of human disease mutations

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

Updated Jun 27, 2026

Abstract

Essence

TCBE-Umax expands zebrafish base editing for faster in vivo testing of human disease variants.

Evidence

In a zebrafish genome-editing platform experiment, engineered TadA cytosine editors improved editing efficiency, context tolerance, PAM compatibility, and were used to phenotype 15 hereditary-hearing-loss VUS.

Caveat

The proof of concept is limited to F0 zebrafish phenotyping of 15 hearing-loss variants, so transfer to other diseases or humans is not shown.

Simplified

Many missense mutations identified in genetic testing are variants of uncertain significance (VUS), not yet classified as either benign or pathogenic. Systematic determination of their functional relevance is a pressing clinical need. CRISPR-mediated base editing can precisely introduce precise variants into model organisms for functional testing, but current editors face efficiency and targeting constraints. We developed TCBE-Umax, a family of TadA-derived cytosine base editors optimized for zebrafish. Engineering the TadA deaminase domain improved editing efficiency and reduced sequence-context bias, expanded PAM compatibility, and minimized bystander edits and indel formation. Our editors achieved efficient biallelic editing, enabling rapid functional assessment of genetic variants in the F(founding) zebrafish. As a proof of concept, we evaluated 15 VUS linked to hereditary hearing loss, determining pathogenicity through phenotypic analysis. With high efficiency and versatility, TCBE-Umax base editors provide a powerful platform for studying genetic variants and disease in vivo. 0

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Highly efficient cytosine base editors for precise modeling of human disease mutations

Abstract

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