数字农科院2.0

CRISPR/Cas9-mediated correction of MITF homozygous point mutation in a Waardenburg syndrome 2A pig model

文献类型： 外文期刊

作者： Yao Jing;Wang Yu;Cao Chunwei;Song Ruigao;Bi Dengfeng;Zhang Hongyong;Li Yongshun;Qin Guosong;Hou Naipeng;Zhang Nan;Zhang Jin;Guo Weiwei;Yang Shiming;Wang Yanfang;Zhao Jianguo

作者机构：

关键词： anophthalmia; base editor; CRISPR/Cas9; gene correction; hearing loss; MITF

期刊名称： Molecular Therapy - Nucleic Acids

ISSN： 2162-2531

年卷期： 2021 年 24 卷

页码：

收录情况： JCR（2021版）

摘要： Gene therapy for curing congenital human diseases is promising, but the feasibility and safety need to be further evaluated. In this study, based on a pig model that carries the c.740T>C (L247S) mutation in MITF with an inheritance pattern and clinical pathology that mimics Waardenburg syndrome 2A (WS2A), we corrected the point mutation by the CRISPR-Cas9 system in the mutant fibroblast cells using single-stranded oligodeoxynucleotide (ssODN) and long donor plasmid DNA as the repair template. By using long donor DNA, precise correction of this point mutation was achieved. The corrected cells were then used as the donor cell for somatic cell nuclear transfer (SCNT) to produce piglets, which exhibited a successfully rescued phenotype of WS2A, including anophthalmia and hearing loss. Furthermore, engineered base editors (BEs) were exploited to make the correction in mutant porcine fibroblast cells and early embryos. The correction efficiency was greatly improved, whereas substantial off-targeting mutations were detected, raising a safety concern for their potential applications in gene therapy. Thus, we explored the possibility of precise correction of WS2A-causing gene mutation by the CRISPR-Cas9 system in a large-animal model, suggesting great prospects for its future applications in treating human genetic diseases. © 2021 The Author(s)

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