Abstract
Hepatitis B virus (HBV) infection remains an important issue of global public health. Although current antiviral therapy has dramatically reduced the mortality and morbidity of chronic hepatitis B (CHB), it fails to cure it. Rebound viremia often occurs after stopping antiviral therapy. Persistent HBV covalently closed circular DNA (cccDNA) and integrated DNA under antiviral therapy form the major barrier to eradication of HBV infection. CRISPR-mediated genome editing has emerged as a promising therapeutic approach to specifically destroy persistent HBV genomes, both cccDNA and integrated DNA, for HBV cure. However, the cleavage of integrated HBV DNA by CRISPR-Cas9 will cause double-strand break (DSB) of host genome, raising a serious safety concern about genome instability and carcinogenesis. The newly developed CRISPR-derived base editors (BEs), which fuse a catalytically disabled nuclease with a nucleobase deaminase enzyme, can be used to permanently inactivate HBV genome by introducing irreversible point mutations for generation of premature stop codons without DSBs of host genome. Although promising, CRISPR-mediated base editing still faces daunting challenges before its clinical application, including the base-editing efficacy, the off-target effect, the difficulty in finding conserved target HBV sequences, and in vivo delivery efficiency. Several strategies have been adopted to optimize the efficiency and specificity of CRISPR-BEs and to improve in vivo delivery efficacy through novel viral and non-viral delivery approaches. Particularly, the non-viral delivery of Cas9 mRNA and ribonucleoprotein by lipid nanoparticles exhibits attractive potential for liver-targeted delivery in clinical. Along with all progress above, the CRISPR-mediated gene therapy will ultimately achieve HBV cure.
Highlights
Publisher’s Note: MDPI stays neutralHepatitis B virus (HBV) infection remains an important issue of global public health [1].More than 240 million persons are chronically infected by HBV [2,3]
The results showed the successful gene editing of persistent HBV infection, the efficacy was only modest, suggesting that there remains room for improvement of in vivo delivery efficiency of cluster regularly interspaced short palindromic repeat (CRISPR)-Cas9
Our study provides the first proof-of-concept that CRISPR/Cas9-mediated base editing can permanently silence HBV gnomes without creating double-strand break (DSB) of host genome (Figure 3) [21]
Summary
Hepatitis B virus (HBV) infection remains an important issue of global public health [1]. More than 240 million persons are chronically infected by HBV [2,3]. Chronic HBV infection often results in progressive liver injury and fibrosis, leading to long-term adverse outcomes, including cirrhosis, hepatic failure and hepatocellular carcinoma (HCC) [3,4,5]. It is estimated that up to 40% of patients with chronic hepatitis B (CHB) require timely antiviral treatment to prevent the detrimental outcomes. Current antiviral therapies, pegylated interferon and nucleos(t)ide analogues (NAs), have dramatically reduced the mortality and morbidity of CHB, neither of them can achieve HBV eradication [6,7]. Accumulative evidence has shown that spontaneous or treatment-induced HBsAg loss can only reduce the risk of HCC, but cannot entirely eliminate it. Chronic HBV infection usually leaves permanent scars in the host genome primarily by integration of viral DNA, which may cause dysregulation of cell growth and eventually increase the carcinogenetic risk of infected hepatocytes [11,12]
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