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Nat Commun. 2018 Jun 14;9(1):2338. doi: 10.1038/s41467-018-04768-7.

Efficient generation of mouse models of human diseases via ABE- and BE-mediated base editing.

Author information

1
Institute of Neuroscience, Chinese Academy of Sciences (CAS) Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, CAS, 200031, Shanghai, China.
2
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Pudong New Area, 201210, Shanghai, China.
3
Institute of Neuroscience, Chinese Academy of Sciences (CAS) Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, CAS, 200031, Shanghai, China. qsun@ion.ac.cn.
4
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Pudong New Area, 201210, Shanghai, China. huangxx@shanghaitech.edu.cn.
5
CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China. huangxx@shanghaitech.edu.cn.

Abstract

A recently developed adenine base editor (ABE) efficiently converts A to G and is potentially useful for clinical applications. However, its precision and efficiency in vivo remains to be addressed. Here we achieve A-to-G conversion in vivo at frequencies up to 100% by microinjection of ABE mRNA together with sgRNAs. We then generate mouse models harboring clinically relevant mutations at Ar and Hoxd13, which recapitulates respective clinical defects. Furthermore, we achieve both C-to-T and A-to-G base editing by using a combination of ABE and SaBE3, thus creating mouse model harboring multiple mutations. We also demonstrate the specificity of ABE by deep sequencing and whole-genome sequencing (WGS). Taken together, ABE is highly efficient and precise in vivo, making it feasible to model and potentially cure relevant genetic diseases.

PMID:
29904106
PMCID:
PMC6002399
DOI:
10.1038/s41467-018-04768-7
[Indexed for MEDLINE]
Free PMC Article

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