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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2016 > Volume 12 Number 8 > Hao Li1, Chunyu Sheng1, Hongbo Liu1, Guangze Liu3, Xinying Du1, Juan Du2, Linsheng Zhan2, Peng Li1, Chaojie Yang1, Lihua Qi1, Jian Wang1, Xiaoxia Yang1, Leili Jia1, Jing Xie1, Ligui Wang1, Rongzhang Hao1, Dongping Xu4, Yigang Tong5, Yusen Zhou5, Jianjun Zhou6, Yansong Sun1, Qiao Li7, Shaofu Qiu1, and Hongbin Song1

An Effective Molecular Target Site in Hepatitis B Virus S Gene for Cas9 Cleavage and Mutational Inactivation

Hao Li1, Chunyu Sheng1, Hongbo Liu1, Guangze Liu3, Xinying Du1, Juan Du2, Linsheng Zhan2, Peng Li1, Chaojie Yang1, Lihua Qi1, Jian Wang1, Xiaoxia Yang1, Leili Jia1, Jing Xie1, Ligui Wang1, Rongzhang Hao1, Dongping Xu4, Yigang Tong5, Yusen Zhou5, Jianjun Zhou6, Yansong Sun1, Qiao Li7, Shaofu Qiu1, and Hongbin Song1
1. Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China. 2. Lab of Blood-Borne Viruses, Beijing Institute of Transfusion Medicine, Beijing, China. 3. Transgenic Engineering Research Laboratory, Infectious Disease Center, Guangzhou 458th Hospital, Guangzhou, China. 4. Research Center for Liver Failure, Beijing 302nd Hospital, Beijing, China. 5. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 6. Gladcan Consulting Company, Beijing, China. 7. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.  Corresponding authors: Prof. Hongbin Song, Institute of Disease Control and Prevention, Academy of Military Medical Science, No. 20 East Street, Fengtai district, Beijing 100071, China. E-mail address: songhb@bmi.ac.cn; Phone/Fax: +86-10-66948475; Dr. Shaofu Qiu, Institute of Disease Control and Prevention, Academy of Military Medical Science, No. 20 East Street, Fengtai district, Beijing 100071, China; e-mail address: qiushf0613@hotmail.com; or Prof. Qiao Li, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Phone:734-615-1977, Email: qiaoli@umich.edu
Abstract :

Chronic hepatitis B infection remains incurable because HBV cccDNA can persist indefinitely in patients recovering from acute HBV infection. Given the incidence of HBV infection and the shortcomings of current therapeutic options, a novel antiviral strategy is urgently needed. To inactivate HBV replication and destroy the HBV genome, we employed genome editing tool CRISPR/Cas9. Specifically, we found a CRISPR/Cas9 system (gRNA-S4) that effectively targeted the HBsAg region and could suppress efficiently viral replication with minimal off-target effects and impact on cell viability. The mutation mediated by CRISPR/Cas9 in HBV DNA both in a stable HBV-producing cell line and in HBV transgenic mice had been confirmed and evaluated using deep sequencing. In addition, we demonstrated the reduction of HBV replication was caused by the mutation of S4 site through three S4 region-mutated monoclonal cells. Besides, the gRNA-S4 system could also reduce serum surface-antigen levels by 99.91 ± 0.05% and lowered serum HBV DNA level below the negative threshold in the HBV hydrodynamics mouse model. Together, these findings indicate that the S4 region may be an ideal target for the development of innovative therapies against HBV infection using CRISPR/Cas9.

Keywords :
HBV infection, CRISPR/Cas9

Date Deposited : 07 Nov 2016 20:02

Last Modified : 07 Nov 2016 20:02

Official URL: http://www.ijbs.com/v12i9

Volume 12, Number 8, August 2016

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