Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats
文献类型：期刊论文
| 作者 | Shao, Yanjiao1,2; Wang, Liren1,2; Guo, Nana1,2; Wang, Shengfei1,2; Yang, Lei1,2; Li, Yajing1,2; Wang, Mingsong1,2; Yin, Shuming1,2; Zeng, Li1,2,3; Zhang, Jiqin1,2 |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2018 |
| 卷号 | 293期号:18页码:6883-6892 |
| ISSN号 | 0021-9258 |
| 关键词 | CRISPR Cas gene therapy liver fibrosis genetic disease Cas9 nickase gene editing genome editing hereditary tyrosinemia |
| DOI | 10.1074/jbc.RA117.000347 |
| 文献子类 | Article |
| 英文摘要 | Hereditary tyrosinemia type I (HTI) is a metabolic genetic disorder caused by mutation of fumarylacetoacetate hydrolase (FAH). Because of the accumulation of toxic metabolites, HTI causes severe liver cirrhosis, liver failure, and even hepatocellular carcinoma. HTI is an ideal model for gene therapy, and several strategies have been shown to ameliorate HTI symptoms in animal models. Although CRISPR/Cas9-mediated genome editing is able to correct the Fah mutation in mouse models, WT Cas9 induces numerous undesired mutations that have raised safety concerns for clinical applications. To develop a new method for gene correction with high fidelity, we generated a Fah mutant rat model to investigate whether Cas9 nickase (Cas9n)-mediated genome editing can efficiently correct the Fah. First, we confirmed that Cas9n rarely induces indels in both on-target and off-target sites in cell lines. Using WT Cas9 as a positive control, we delivered Cas9n and the repair donor template/single guide (sg)RNA through adenoviral vectors into HTI rats. Analyses of the initial genome editing efficiency indicated that only WT Cas9 but not Cas9n causes indels at the on-target site in the liver tissue. After receiving either Cas9n or WT Cas9-mediated gene correction therapy, HTI rats gained weight steadily and survived. Fah-expressing hepatocytes occupied over 95% of the liver tissue 9 months after the treatment. Moreover, CRISPR/Cas9-mediated gene therapy prevented the progression of liver cirrhosis, a phenotype that could not be recapitulated in the HTI mouse model. These results strongly suggest that Cas9n-mediated genome editing is a valuable and safe gene therapy strategy for this genetic disease. |
| 学科主题 | Biochemistry & Molecular Biology |
| WOS关键词 | IN-VIVO ; NTBC TREATMENT ; MOUSE MODEL ; MICE ; VECTORS ; REPAIR ; PATHOPHYSIOLOGY ; TYPE-1 |
| 语种 | 英语 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| WOS记录号 | WOS:000431487300021 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/1020]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China; 2.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China; 3.Bioray Labs Inc, Shanghai 200241, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200031, Peoples R China; 5.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, CAS Key Lab Nutr & Metab,Inst Nutr Sci, Shanghai 200031, Peoples R China; 6.Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Pediat Urol, Shanghai 200092, Peoples R China; 7.Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Dept Mol & Cellular Med, Houston, TX 77030 USA, |
| 推荐引用方式 GB/T 7714 | Shao, Yanjiao,Wang, Liren,Guo, Nana,et al. Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(18):6883-6892. |
| APA | Shao, Yanjiao.,Wang, Liren.,Guo, Nana.,Wang, Shengfei.,Yang, Lei.,...&,.(2018).Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats.JOURNAL OF BIOLOGICAL CHEMISTRY,293(18),6883-6892. |
| MLA | Shao, Yanjiao,et al."Cas9-nickase-mediated genome editing corrects hereditary tyrosinemia in rats".JOURNAL OF BIOLOGICAL CHEMISTRY 293.18(2018):6883-6892. |
入库方式： OAI收割
来源：上海营养与健康研究所
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