美国芝加哥大学Weixin Tang课题组取得一项新突破。他们的研究发现腺嘌呤碱基编辑器（ABE）变体扩展了其兼容性。2024年1月2日出版的《自然—生物技术》发表了这项成果。

研究人员对大肠杆菌转运核糖核酸特异性腺苷脱氨酶（TadA）进行了进化，生成了TadA8r，它能将强效脱氧腺苷脱氨扩展到RA（R=A或G），处理GA的速度比TadA8.20和TadA8e（迄今报道的两种最活跃的TadA变体）更快。ABE8r由TadA8r和化脓性链球菌Cas9切分酶组成，扩展了原位相邻远端的编辑窗口，在编辑人类基因组中与疾病相关的G:C到A:T转换方面优于ABE7.10、ABE8.20和ABE8e，而且脱靶情况可控。

研究人员展示了ABE8r可对现有编辑器难以实现的临床相关位点进行编辑，包括PCSK9的相关位点（其破坏会降低低密度脂蛋白胆固醇）和ABCA4-p.Gly1961Glu中的位点（Stargardt病最常见的突变）。

据了解，腺嘌呤碱基编辑器是一种精确的基因编辑工具，可通过脱氧肌苷中间体将A:T对转化为G:C。当目标A位于TA序列时，现有ABE的编辑效率最好。

附：英文原文

Title: An adenine base editor variant expands context compatibility

Author: Xiao, Yu-Lan, Wu, Yuan, Tang, Weixin

Issue&Volume: 2024-01-02

Abstract: Adenine base editors (ABEs) are precise gene-editing agents that convert A:T pairs into G:C through a deoxyinosine intermediate. Existing ABEs function most effectively when the target A is in a TA context. Here we evolve the Escherichia coli transfer RNA-specific adenosine deaminase (TadA) to generate TadA8r, which extends potent deoxyadenosine deamination to RA (R=A or G) and is faster in processing GA than TadA8.20 and TadA8e, the two most active TadA variants reported so far. ABE8r, comprising TadA8r and a Streptococcus pyogenes Cas9 nickase, expands the editing window at the protospacer adjacent motif-distal end and outperforms ABE7.10, ABE8.20 and ABE8e in correcting disease-associated G:C-to-A:T transitions in the human genome, with a controlled off-target profile. We show ABE8r-mediated editing of clinically relevant sites that are poorly accessed by existing editors, including sites in PCSK9, whose disruption reduces low-density lipoprotein cholesterol, and ABCA4-p.Gly1961Glu, the most frequent mutation in Stargardt disease.

DOI: 10.1038/s41587-023-01994-3

Source: https://www.nature.com/articles/s41587-023-01994-3