CRISPR-Cas9 Gene Editing of Hepatitis B Virus in Chronically Infected Humanized Mice

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2021 Jan 21

PMID 33473359

Citations 45

Authors

Daniel Stone

Kelly R Long

Michelle A Loprieno

Harshana S De Silva Feelixge

Elizabeth J Kenkel

R Matt Liley

Stephen Rapp

Pavitra Roychoudhury

Thuy Nguyen

Laurence Stensland

Rossana Colon-Thillet

Lindsay M Klouser

Nicholas D Weber

Connie Le

Jessica Wagoner

Erin A Goecker

Alvason Zhenhua Li

Karsten Eichholz

Lawrence Corey

D Lorne Tyrrell

Alexander L Greninger

Meei-Li Huang

Stephen J Polyak

Martine Aubert

John E Sagartz

Keith R Jerome

Affiliations

Soon will be listed here.

Abstract

Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR- ()Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir. Gene editing was detected in livers of five of eight HBV-specific AAV-Cas9-treated mice, but not control mice, and mice with detectable HBV gene editing showed higher levels of Cas9 delivery to HBV human hepatocytes than those without gene editing. HBV-specific AAV-Cas9 therapy significantly improved survival of human hepatocytes, showed a trend toward decreasing total liver HBV DNA and cccDNA, and was well tolerated. This work provides evidence for the feasibility and safety of gene editing for chronic HBV infections, and it suggests that with further optimization, this approach may offer a plausible way to treat or even cure chronic HBV infections.

Citing Articles

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