Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

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

Subsequent work assessed utility of AAV vector for delivery of interferon expression cassettes. Berraondo et al. tested intrahepatic and intramuscular expression of AAV8-delivered wIFN-α5 following administration to woodchucks chronically infected with WHV [96] . Interferon was readily expressed at both sites of delivery, but expression in the liver was superior. Furthermore, only expression of interferon from the liver was associated with an antiviral response. Although the higher vector dose had a more pronounced antiviral effect, it was also associated with greater toxicity. The woodchuck with the greatest decrease in viremia exhibited such severe side effects that it required euthanasia prior to completion of the study. Another limitation of the approach was the transient nature of the antiviral effect, which was attributed to immune-mediated clearance of AAV-infected hepatocytes. To improve their delivery system Berraondo et al. developed a modified IFN-α which was fused to sequences encoding apolipoprotein A (InterApo) [97] . Initial assessment demonstrated that InterApo exhibited an improved safety profile while maintaining antiviral efficacy in HBV transgenic mice. In the woodchucks chronically infected with WHV, AAV-delivered InterApo was well-tolerated but showed little efficacy. This was attributed to the high WHV load in woodchucks with chronic hepatitis. Pre-treatment of woodchucks with the NA entecavir with subsequent administration of AAV-InterApo facilitated immune-mediated clearance. However, the antiviral effect was transient and viral rebound to pre-treatment levels eventually occurred.