The Role of RNA Interference in Functional Cure Strategies for Chronic Hepatitis B

Abstract

Purpose of Review Current treatments for chronic hepatitis B (CHB) are associated with low rates of cure. Functional cure has been accepted as a viable treatment end point in CHB. There have been substantial advances in the field of RNA interference (RNAi) therapeutics across a wide range of specialties, and the clinical pipeline now encompasses CHB. This review will highlight some of the challenges in therapeutic development, the data for RNAi in CHB, and future directions for the field. Recent Findings Early phase clinical trials have reported good safety data for RNAi therapies in CHB and demonstrated significant reductions in quantitative HBsAg levels (qHBsAg). Animal models however suggest that in HBeAg-negative individuals, HBsAg may be derived from hepatitis B DNA integrated into the host genome, which cannot be targeted by current RNAi therapies, and may prove to be a limitation. Preliminary data is being presented from combination therapy, which may result in more robust reductions in qHBsAg; however, trials are in the early stages of recruitment. Summary Despite promising data that RNAi may be an effective therapeutic strategy in CHB, it is unlikely to be in the form of monotherapy. The goal for the community will be to find the right combination of RNAi therapy with other antiviral or immunomodulatory agents, to achieve functional cure with a cessation of therapy. Early phase clinical trials are continuing to recruit, and data from combination studies will provide a “pivot point” in determining whether RNAi therapies can provide a backbone to finite duration and curative CHB regimens.

Depleting hepatitis B virus relaxed circular DNA is necessary for resolution of infection by CRISPR-Cas9

“… 34 Despite the promising results RNAi therapies are unlikely to become monotherapies, so revealing new, effective drug combinations is of critical importance. 35 RNAi therapies are currently studied in combination with traditional nucleot(s)ide analogs, peg-interferon-α, and viral entry inhibitors 36 to improve treatment outcomes and achieve a cure or stable post-treatment control of HBV replication. In light of our results, the use of RNAi therapies may have benefits compared with nucleot(s)ide analogs by effectively destabilizing pgRNA and countering HBV cccDNA de novo formation.…”

Viral hepatitis: Innovations and expectations

“…Post-transcriptional inhibitors: Synthetic small interfering RNAs (iRNA) or silencing RNAs, are a class of non-coding RNAs that recognize complementary viral mRNA and pgRNA, inducing mRNA degradation after transcription and preventing translation[ 25 ]. In the contest of HBV infection, small iRNAs bind HBV mRNA in hepatocytes and induce its degradation.…”

Cellular and Molecular Mechanisms Underlying Scope and Limitation of Ongoing and Innovative Therapies for Treating Chronic Hepatitis B

“…Overall, this may reduce the HBV DNA levels in the sera. RNAi has been shown to block HBsAg production [26]. The role of HBsAg in the immune regulation of CHB patients has been shown, and thus, it is assumed that, by blocking HBsAg production, RNAi may restore the host immunity.…”