Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

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

Despite the importance of HBV DNA epigenetic modification for disease progression, evidence supporting the feasibility of using epigenetic modifiers against HBV is currently limited. Few studies have taken advantage of the sequence-specific binding domains of designer nucleases for their repurposing as epigenetic silencers. By replacing a nuclease domain of a designer nuclease with an epigenetic modulator, ZFs, TALEs, and CRISPR/Cas have usually been modified for epigenetic editing of endogenous genes (reviewed by [90] ). However, this strategy is theoretically applicable to targeted epigenetic modification of HBV DNA. One study reported successful epigenetic editing of HBV DNA after fusing the catalytic domain of DNMT3a to a ZF that targeted the HBx promoter sequence [79] . The engineered sequence caused methylation of targeted CpG sites, downregulation of viral mRNAs and proteins, and a decrease in viral replication in cell culture and in HBV transgenic mice. Repressors based on the Krüppel associated box (KRAB) domain have also been investigated as ZF [80] and TALE [81] fusions. Although these KRAB-repressors inhibit viral replication, verification of heterochromatin formation, which is important to achieve permanent gene silencing, remains to be confirmed. Studies demonstrating antiviral efficacy and sustainability of epigenetic editors on HBV replication are preliminary. However, investigations aimed at developing the approach to treat other chronic viral infections, such as HIV [91] , are more advanced. Moreover, Food and Drug Administration (FDA) approval of HDAC inhibitors for cancer treatment [92] supports the notion that epigenetic editing has clinical potential for treatment of HBV infection.