RNA interference as a novel treatment strategy for chronic hepatitis B infection

Abstract

Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. Functional cure of CHB, defined as sustainable hepatitis B surface antigen (HBsAg) seroclearance, is associated with improved clinical outcomes.However, functional cure is rarely attainable by current treatment modalities.RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB.RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/ II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2 -2.5 log. Incidences of HBsAg seroclearance after siRNA therapy have also been reported. ASOs have also been studied in early phase trials, and a phase Ib study using frequent dosing regimen within 4 weeks could achieve similar HBsAg reduction of 2 log from baseline. Given the established efficacy and safety of nucleos(t)ide analogues (NAs), future RNAi regimens will likely include NA backbone. While the current evidence on RNAi appears promising, it remains undetermined whether the potent HBsAg reduction by RNAi can result in a high rate of HBsAg seroclearance with durability. Data on RNAi from phase IIb/III trials are keenly anticipated.

KASL clinical practice guidelines for management of chronic hepatitis B

“…The siRNA guide strand directs the RNA-induced silencing complex (RISC) to the complementary target RNA, which is then cleaved by the Argonaute protein present in the RISC [ 221 , 222 ]. Lipid nanoparticles or N-acetylgalactosamine (GalNac/NAG)-linked particles are used to deliver these agents to hepatocytes [ 222 , 223 ].…”

Antigen Load and T Cell Function: A Challenging Interaction in HBV Infection

“…Although the effect of antigen decline on T cell function still remains a debated issue, strategies to lower the antigen burden before immune cell stimulation may be successful in optimizing lymphocyte responsiveness to exogenously administered antigens, for example by vaccine therapies. These strategies include RNA interfering compounds (RNAi) targeting viral transcripts [ 54 ], nucleic acid polymers (NAP) that inhibit HBsAg release [ 55 , 56 , 57 ], or anti-HBV humanized monoclonal antibodies [ 58 ] ( Table 1 ).…”

Hepatitis B x (HBx) as a Component of a Functional Cure for Chronic Hepatitis B

“…Small-interfering RNAs (siRNAs) that block the expression of one or more HBV genes are under development [ 31 ] ( Table 1 ), but it is not clear whether they could be delivered to all infected cells, at sufficient concentrations, and for a sustained period of time, to be therapeutically useful. It is too early to know whether they could augment nucleoside analogs or other therapeutic approaches.…”