Human 8-cell embryos enable efficient induction of disease-preventive mutations without off-target effect by cytosine base editor

文献类型： 外文期刊

第一作者： Wei, Yinghui

作者： Wei, Yinghui;Zhang, Meiling;Li, Wen;Wei, Yinghui;Hu, Jing;Zhou, Yingsi;Xue, Mingxing;Liu, Yuanhua;Yang, Hui;Xu, Chunlong;Zhang, Meiling;Wang, Dongshuang;Zhou, Yin;Yao, Ning;Du, Yanzhi;Yin, Jianhang;Hu, Jiazhi;Liu, Hongbin;Zhang, Meiling;Feng, Hu;Zhou, Ling;Li, Zhifang;Zhang, Zhiguo

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关键词： human embryo; APOE4; disease-preventive mutations; base editor

期刊名称：PROTEIN & CELL （ 影响因子：21.1； 五年影响因子：16.7 ）

ISSN： 1674-800X

年卷期： 2023 年 14 卷 6 期

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收录情况： SCI

摘要： Approximately 140 million people worldwide are homozygous carriers of APOE4 (epsilon 4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible epsilon 4 allele copies were converted to the AD-neutral epsilon 3 allele in human epsilon 4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.

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