Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

Bloom, Kristie; Maepa, Mohube Betty; Ely, Abdullah; Arbuthnot, Patrick

Expression of IFN-α-encoding sequences in the liver has been explored as a means of improving anti-HBV efficacy and reducing side effects of conventional IFN-α treatment. One of the first studies explored expression of murine IFN-α2 under transcriptional control of the liver-specific transthyretin promoter [93] . The IFN-α expression construct was delivered to the livers of mice using a helper-dependent adenovirus (HDAd), and the interferon response genes 2 ,5 -oligoadenylate synthetase and tumor necrosis factor α (TNF-α) were effectively induced. As a surrogate for assessing anti-HBV potential of this system the authors challenged mice with a murine coronavirus, MHV-2. Mice pre-treated with the HDAd carrying IFN-α were protected from infection and did not exhibit any toxic side effects. Fiedler et al. assessed usefulness of a gene therapy-based approach to express IFN-α or IFN-γ in a woodchuck hepatitis virus (WHV) model of HBV infection [94] . Sequences encoding woodchuck IFN-α or IFN-γ (wIFN-α or wIFN-γ) were delivered to woodchucks with an HDAd. In animals chronically infected with WHV, viral replicative intermediates in the liver and serum were considerably diminished. This was a significant finding as WHV maintains very high viral loads in its host, much higher than in chronic HBV carriers. Furthermore, no obvious side effects were observed and wIFN-α expression lasted for at least a year. In contrast to the promising results achieved with wIFN-α, expression of wIFN-γ did not have a significant effect on WHV replication. This differs from the results of Dumortier et al. who demonstrated that IFN-γ expression was able to limit HBV replication in mice [95] .