Despite the availability of an effective vaccine against hepatitis B virus (HBV), chronic infection with the virus remains a major global health concern. Current drugs against HBV infection are limited by emergence of resistance and rarely achieve complete viral clearance. This has prompted vigorous research on developing better drugs against chronic HBV infection. Advances in understanding the life cycle of HBV and improvements in gene-disabling technologies have been impressive. This has led to development of better HBV infection models and discovery of new drug candidates. Ideally, a regimen against chronic HBV infection should completely eliminate all viral replicative intermediates, especially covalently closed circular DNA (cccDNA). For the past few decades, nucleic acid-based therapy has emerged as an attractive alternative that may result in complete clearance of HBV in infected patients. Several genetic anti-HBV strategies have been developed. The most studied approaches include the use of antisense oligonucleotides, ribozymes, RNA interference effectors and gene editing tools. This review will summarize recent developments and progress made in the use of gene therapy against HBV.

Gene editinG and Gene ReGulation iistimulation paralleled that of endogenous CD40L in unedited T-cells. Additionally, activated T-cells expressing edited CD40L were able to bind CD40-Ig similar to unedited cells. When T-cells from X-HIGM patients were edited in this fashion, CD40L expression and CD40-Ig binding was restored, and repaired activated X-HIGM T-cells induced the expression of early activation markers and class switching of naïve B-cells in vitro. Finally, we found no differences in TCR repertoire or engraftment and stability in NSG mice between T cells that underwent gene editing vs. unedited cells. These results demonstrate the feasibility of site-directed gene repair to restore normally regulated CD40L protein expression and functional T-cell help.