等位基因
生物
胚胎
人类基因组
遗传学
疾病
胚泡
基因
人类遗传学
计算生物学
生物信息学
基因组
医学
胚胎发生
内科学
作者
Yinghui Wei,Meiling Zhang,Jing Hu,Yingsi Zhou,Mingxing Xue,Jianhang Yin,Yuanhua Liu,Hu Feng,Ling Zhou,Zhifang Li,Dongshuang Wang,Zhiguo Zhang,Yin Zhou,Hongbin Liu,Ning Yao,Erwei Zuo,Jiazhi Hu,Yanzhi Du,Wen Li,Chunlong Xu,Hui Yang
标识
DOI:10.1093/procel/pwac043
摘要
Abstract Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), 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 non-carriers. 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 ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-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 (SLE) and familial hypercholesterolemia (FH). 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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