Evolved cytidine and adenine base editors with high precision and minimized off-target activity by a continuous directed evolution system in mammalian cells

Na Zhao, Jian Zhou (), Tianfu Tao, Qi Wang, Jie Tang, Dengluan Li, Shixue Gou, Zhihong Guan, Joshua Seun Olajide, Jiejing Lin, Shuo Wang, Xiaoping Li, Jiankui Zhou, Zongliang Gao () and Gang Wang ()
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Na Zhao: Guangzhou University
Jian Zhou: Guangzhou University
Tianfu Tao: Guangzhou University
Qi Wang: Guangzhou University
Jie Tang: Guangzhou University
Dengluan Li: Guangzhou University
Shixue Gou: Guangzhou National Laboratory
Zhihong Guan: Guangzhou University
Joshua Seun Olajide: Guangzhou University
Jiejing Lin: Guangzhou University
Shuo Wang: Guangzhou University
Xiaoping Li: Sun Yat-sen University
Jiankui Zhou: Guangzhou University
Zongliang Gao: Guangzhou Medical University
Gang Wang: Guangzhou University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Continuous directed evolution of base editors (BEs) has been successful in bacteria cells, but not yet in mammalian cells. Here, we report the development of a Continuous Directed Evolution system in Mammalian cells (CDEM). CDEM enables the BE evolution in a full-length manner with Cas9 nickase. We harness CDEM to evolve the deaminases of cytosine base editor BE3 and adenine base editors, ABEmax and ABE8e. The evolved cytidine deaminase variants on BE4 architecture show not only narrowed editing windows, but also higher editing purity and low off-target activity without a trade-off in on-targeting activity. The evolved ABEmax and ABE8e variants exhibit narrowed or shifted editing windows to different extents, and lower off-target effects. The results illustrate that CDEM is a simple but powerful approach to continuously evolve BEs without size restriction in the mammalian environment, which is advantageous over continuous directed evolution system in bacteria cells.

Date: 2024
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DOI: 10.1038/s41467-024-52483-3

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