Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.

Automated summary

Three types of oligonucleotide-based medicines, namely antisense oligonucleotides (ASOs), synthetic interfering RNA (siRNA), and nucleic acid polymers (NAPs), are being developed for the treatment of chronic HBV infection. ASOs and siRNA are designed to degrade HBV mRNA, while NAPs inhibit the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA in liver diseases has provided a solid understanding of their pharmacodynamics, tissue accumulation, pharmacological effects, off-target effects, and the impact of chemical modifications and delivery approaches. However, the clinical assessment of these compounds in chronic HBV infection is complicated by various delivery approaches and the lack of consideration for their function in other liver diseases and off-target effects in other viral infections.