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北京大魏文胜研究小组使用mitoBE对人类线粒体DNA进行链式选择性碱基编辑。2023年5月22日，《自然—生物技术》杂志在线发表了这项成果。

研究人员提出了线粒体DNA碱基编辑器（mitoBE），它结合了一个转录激活器样效应器（TALE）融合的缺口酶和一个脱氨酶，用于线粒体DNA的精确碱基编辑。将线粒体定位的、可编程的TALE结合蛋白与缺口酶MutH或Nt.BspD6I(C)以及单链DNA特异性腺嘌呤脱氨酶TadA8e或胞嘧啶脱氨酶ABOBEC1和UGI相结合，研究人员实现了A到G或C到T的碱基编辑，效率高达77%，并且特异性强。研究人员发现mitoBE是具有DNA链选择性的线粒体碱基编辑，编辑结果更有可能保留在非切口DNA链上。此外，研究人员通过传递编码在环状RNA中的mitoBE，纠正了患者衍生细胞中的致病性线粒体DNA突变。mitoBE提供了一种精确、高效的DNA编辑工具，对线粒体遗传病的治疗具有广泛的适用性。

据了解，人类的一些线粒体疾病是由点突变引起的，这些突变可以通过碱基编辑器来纠正，但将CRISPR引导RNA送入线粒体很困难。

附：英文原文

Title: Strand-selective base editing of human mitochondrial DNA using mitoBEs

Author: Yi, Zongyi, Zhang, Xiaoxue, Tang, Wei, Yu, Ying, Wei, Xiaoxu, Zhang, Xue, Wei, Wensheng

Issue&Volume: 2023-05-22

Abstract: A number of mitochondrial diseases in humans are caused by point mutations that could be corrected by base editors, but delivery of CRISPR guide RNAs into the mitochondria is difficult. In this study, we present mitochondrial DNA base editors (mitoBEs), which combine a transcription activator-like effector (TALE)-fused nickase and a deaminase for precise base editing in mitochondrial DNA. Combining mitochondria-localized, programmable TALE binding proteins with the nickase MutH or Nt.BspD6I(C) and either the single-stranded DNA-specific adenine deaminase TadA8e or the cytosine deaminase ABOBEC1 and UGI, we achieve A-to-G or C-to-T base editing with up to 77% efficiency and high specificity. We find that mitoBEs are DNA strand-selective mitochondrial base editors, with editing results more likely to be retained on the nonnicked DNA strand. Furthermore, we correct pathogenic mitochondrial DNA mutations in patient-derived cells by delivering mitoBEs encoded in circular RNAs. mitoBEs offer a precise, efficient DNA editing tool with broad applicability for therapy in mitochondrial genetic diseases.

DOI: 10.1038/s41587-023-01791-y

Source: https://www.nature.com/articles/s41587-023-01791-y

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex