{"id":"doi:10.1002/advs.77657","kind":"article","title":"Engineered Transformer Base Editor with Enhanced Editing Efficiency","authors":["Chen B","Liang L","Xu R","Wang T","Chen H","Lu D"],"author_count":6,"year":2026,"published":"2026-09-10","venue":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","cited_by":0,"doi":"10.1002/advs.77657","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1002/advs.77657","archive_url":"https://space-kitty.com/papers/doi:10.1002/advs.77657","updated":null,"pmid":"42723179","pmcid":"PMC13562778","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13562778/pdf","abstract":"Canonical cytosine base editors (CBEs) achieve precise C-to-T conversions without inducing DNA double-strand breaks (DSBs), yet their clinical potential remains hampered by substantial off-target (OT) mutations. The recently developed transformer base editor (tBE) significantly reduces both genomic and transcriptomic OT mutations by using a cleavable deoxycytidine deaminase inhibitor (dCDI) domain. However, the modest base editing efficiency limits its broader applications. Here, through rational deaminase engineering and fusion of a uracil DNA glycosylase inhibitor (UGI) domain, we developed the engineered tBE (etBE). The etBE exhibited substantially enhanced editing efficiencies compared with the parental tBE (up to 35.11-fold improvement), while maintaining high editing fidelity and background levels of OT mutations. As a therapeutic proof-of-concept, dual adeno-associated virus (AAV)-mediated delivery of etBE targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-established therapeutic target for cardiovascular diseases, was evaluated in a humanized mouse model. The treatment achieved efficient in vivo base editing (up to 35.13%), resulting in substantial reductions in plasma PCSK9 protein (24%) and low-density lipoprotein cholesterol (LDL-C) levels (33%), while inducing only minimal OT mutations. Collectively, etBE represents a highly efficient and specific base editing platform with enormous potential for both basic research and clinical applications.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Engineered Transformer Base Editor with Enhanced Editing Efficiency\" by Chen B, Liang L, Xu R et al., https://doi.org/10.1002/advs.77657, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}