Chapter 6 - Gene Therapy for Chronic Hepatitis B Virus Infection

Abstract

Chronic infection with hepatitis B virus (HBV) occurs in 6% of the world's population. These carriers of the virus are at high risk for the life-threatening complications of cirrhosis and liver cancer. Although effective vaccines are available to prevent HBV infection, they are of no use to individuals who are already infected with the virus. Therefore, complications of chronic HBV infection are likely to remain a significant public health problem for some time. Stability of the HBV covalently closed circular DNA (cccDNA), together with resistance of this replication intermediate to licensed therapies, are the main reasons for the limited success of currently available treatment interventions. Gene therapy approaches, particularly using exogenous RNA interference (RNAi) activators and derivatives of DNA sequence-specific proteins, have shown potential as HBV therapeutics. Synthetic and expressed RNAi activators have been used successfully to inhibit HBV replication in cell culture and murine models of the infection. A candidate drug comprising a short interfering RNA conjugate is currently in phase II of clinical trial. Although efficacy against the virus is impressive, it remains to be established whether gene silencing will be curative of persistent HBV infection. In one of the first studies using sequence-specific DNA binding proteins, zinc finger proteins (ZFPs) were shown to inhibit transcription from duck HBV cccDNA. Subsequent investigations showed that coupling FokI endonuclease elements to ZFPs or transcription activator-like effectors achieved specific cleavage of HBV DNA, with resultant disabling of viral gene expression. This was an important development in HBV gene therapy because it demonstrated that inactivation of the problematic viral cccDNA replication intermediate is feasible.