Protein-nucleic acid language model-assisted design of precise and compact adenine base editor

Adenine base editors (ABEs) are powerful tools for gene therapy. However, efficient version of ABEs (e.g. ABE8e) always induce excessive bystander and off-target editing events and are large in size, hindering their potential in clinical disease treatment. Here, we develop a pre-trained Protein-Nucleic Acid Constrained Language Model to design ABE8e with high activity, reduced editing window and decreased size. By further engineering, the smallest ABE8e- PNLM-pcABE- with a 27% size reduction, exhibits high activity, precise 3-nt editing window, and reduced off-target events near background level in HEK293T cells. Compared to ABE8e, PNLM-pcABE has up to 133.5-fold precision improvement in pathogenic mutation correction. By PNLM-pcABE, the albino mouse model carrying desired base mutation is nearly 100% obtained via zygotes microinjection and the expression of PCSK9 substantially decreases in mice receiving in vivo delivery with lipid nanoparticle (LNP), indicating their great potential in gene therapy and disease modeling.

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Publication Details

Journal
Nature Communications
Published
2025-12-13
DOI
https://doi.org/10.1038/s41467-025-65311-z
Primary Topic
CRISPR and Genetic Engineering
Type
article
Field-Weighted Citation Impact
0.00

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article

Protein-nucleic acid language model-assisted design of precise and compact adenine base editor

Qiuyu Cao, Xiyu Ge, Yinuo Li, Shengfang Wang et al.
Nature Communications
CRISPR and Genetic Engineering
article

Protein-nucleic acid language model-assisted design of precise and compact adenine base editor

Qiuyu Cao, Xiyu Ge, Yinuo Li, Shengfang Wang, Ziyi Zhang, Yang Zhang, Xiaogang Wang, Yang Li, Xiaohui Zhang, Jingxuan Ren, Jiawei Yao
article en

Abstract

Adenine base editors (ABEs) are powerful tools for gene therapy. However, efficient version of ABEs (e.g. ABE8e) always induce excessive bystander and off-target editing events and are large in size, hindering their potential in clinical disease treatment. Here, we develop a pre-trained Protein-Nucleic Acid Constrained Language Model to design ABE8e with high activity, reduced editing window and decreased size. By further engineering, the smallest ABE8e- PNLM-pcABE- with a 27% size reduction, exhibits high activity, precise 3-nt editing window, and reduced off-target events near background level in HEK293T cells. Compared to ABE8e, PNLM-pcABE has up to 133.5-fold precision improvement in pathogenic mutation correction. By PNLM-pcABE, the albino mouse model carrying desired base mutation is nearly 100% obtained via zygotes microinjection and the expression of PCSK9 substantially decreases in mice receiving in vivo delivery with lipid nanoparticle (LNP), indicating their great potential in gene therapy and disease modeling.

Nature CommunicationsVol. 16(1)
National University of Singapore (SG), Baylor College of Medicine (US), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Third Affiliated Hospital of Southern Medical University (CN), National University Cancer Institute, Singapore (SG), Suzhou Institute of Systems Medicine (CN)
National Natural Science Foundation of China, East China Normal University, Tsinghua University, Chinese Academy of Medical Sciences
Openalex Percentile: Top 64%
CRISPR and Genetic Engineering
DOIOpen Access PDFOpenAlex
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