Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing

doi:10.1038/s41392-022-00893-4

	Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing
	Zheng, Ziwen 1,2,3; Li, Guo 4,5; Cui, Chong 1,2,3; Wang, Fang 1,2,3; Wang, Xiaohan 6; Xu, Zhijiao 1,2,3; Guo, Huiping 1,2,3; Chen, Yuxin 1,2,3; Tang, Honghai 1,2,3; Wang, Daqi 1,2,3; Huang, Mingqian 7,8; Chen, Zheng Yi 7,8; Huang, Xingxu9,10 ; Li, Huawei 1,2,3,11; Li, Geng Lin 1,2,3; Hu, Xiaoxiang 4,5; Shu, Yilai 1,2,3
	2022-12-01
发表期刊	SIGNAL TRANSDUCTION AND TARGETED THERAPY
ISSN	2095-9907
EISSN	2059-3635
卷号	7 期号:1
发表状态	已发表
DOI	10.1038/s41392-022-00893-4
摘要	CRISPR/RfxCas13d (CasRx) editing system can specifically and precisely cleave single-strand RNAs, which is a promising treatment for various disorders by downregulation of related gene expression. Here, we tested this RNA-editing approach on Beethoven (Bth) mice, an animal model for human DFNA36 due to a point mutation in Tmc1. We first screened 30 sgRNAs in cell cultures and found that CasRx with sgRNA3 reduced the Tmc1 transcript by 90.8%, and the Tmc1 wild type transcript (Tmc1) by 44.3%. We then injected a newly developed AAV vector (AAV-PHP.eB) based CasRx into the inner ears of neonatal Bth mice, and we found that Tmc1 was reduced by 70.2% in 2 weeks with few off-target effects in the whole transcriptome. Consistently, we found improved hair cell survival, rescued hair bundle degeneration, and reduced mechanoelectrical transduction current. Importantly, the hearing performance, measured in both ABR and DPOAE thresholds, was improved significantly in all ages over 8 weeks. We, therefore, have validated the CRISPR/CasRx-based RNA editing strategy in treating autosomal-dominant hearing loss, paving way for its further application in many other hereditary diseases in hearing and beyond.
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收录类别	SCIE
语种	英语
Scopus 记录号	2-s2.0-85126424071
来源库	Scopus
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/165030
专题	生命科学与技术学院_PI研究组_黄行许组
作者单位	1.ENT Institute and Department of Otorhinolaryngology,Eye & ENT Hospital,State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Fudan University,Shanghai,200031,China 2.Institutes of Biomedical Sciences,Fudan University,Shanghai,200032,China 3.NHC Key Laboratory of Hearing Medicine (Fudan University),Shanghai,200032,China 4.State Key Laboratory of Agrobiotechnology,China Agricultural University,Beijing,100193,China 5.College of Biological Sciences,China Agricultural University,Beijing,100193,China 6.School of Life Science and Technology,Southeast University,Nanjing,210096,China 7.Department of Otolaryngology-Head and Neck Surgery,Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience,Harvard Medical School,Boston,02115,United States 8.Eaton-Peabody Laboratory,Massachusetts Eye and Ear Infirmary,Boston,02114,United States 9.School of Life Science and Technology,ShanghaiTech University,Shanghai,200031,China 10.CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai,200031,China 11.Institutes of Brain Science and the Collaborative Innovation Center for Brain Science,Fudan University,Shanghai,200031,China
推荐引用方式 GB/T 7714	Zheng, Ziwen,Li, Guo,Cui, Chong,et al. Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2022,7(1).
APA	Zheng, Ziwen.,Li, Guo.,Cui, Chong.,Wang, Fang.,Wang, Xiaohan.,...&Shu, Yilai.(2022).Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing.SIGNAL TRANSDUCTION AND TARGETED THERAPY,7(1).
MLA	Zheng, Ziwen,et al."Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing".SIGNAL TRANSDUCTION AND TARGETED THERAPY 7.1(2022).