Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation

文献类型： 外文期刊

第一作者： Liu, Jing

作者： Liu, Jing;Yang, Fayu;Shang, Lu;Cai, Shuo;Wu, Yuting;Liu, Yingchun;Zhang, Lifang;Fei, Chenzhong;Wang, Mi;Gu, Feng;Liu, Jing;Yang, Fayu;Shang, Lu;Cai, Shuo;Wu, Yuting;Liu, Yingchun;Zhang, Lifang;Fei, Chenzhong;Wang, Mi;Gu, Feng

作者机构：

关键词： ABE; atherosclerosis; gene editing; hypercholesterolemia; low-density lipoprotein receptor

期刊名称：FASEB JOURNAL （ 影响因子：4.8； 五年影响因子：5.2 ）

ISSN： 0892-6638

年卷期： 2024 年 38 卷 6 期

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收录情况： SCI

摘要： Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. Ldlr(W490X/W490X) mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

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