Durable inhibition of hepatitis B virus replication and antigenemia using a subcutaneously administered siRNA agent in preclinical models

Lee, A.C.H.; Heyes, J.; Ye, X.; Holland, Robert E.; Thi, Emily P.; Wood, Michael L.; Judge, Adam D.; Snead, Nicholas M.; Martin, Aaron; Sofia, Michael J.

doi:10.1016/s0168-8278(18)30254-x

Cited by 9 publications

(8 citation statements)

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“…“A functional cure”, which is characterized by HBsAg loss and/or HBsAg seroconversion, is the ideal treatment goal for HBV infection [15] . RNAi, with the ability to degrade mRNA in a sequence-specific manner, shows unique capabilities in reducing HBsAg and HBeAg [9 , 22 , 23] . Preclinical and clinical studies have also confirmed that siRNA-based treatment could significantly reduce the levels of HBsAg and HBeAg in vivo and improve host immune function [24] .…”

Section: Discussionmentioning

confidence: 99%

“…RNA interference (RNAi) technology can specifically degrade target RNA and has shown potential curative effects in anti-HBV research by significantly reducing HBsAg levels and promoting the elimination of HBsAg. A variety of small interfering RNA (siRNA)-based drugs targeting HBV sequences are currently undergoing assessment in phase I and II clinical trials and have shown promising prospects [7 – 9] . RNAi is an evolutionarily conserved antiviral mechanism that relies on siRNA of 21–23 base-pair-long double-stranded RNA.…”

Section: Introductionmentioning

confidence: 99%

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Immunostimulatory siRNA with a uridine bulge leads to potent inhibition of HBV and activation of innate immunity

Lan

Wei

et al. 2021

Virol J

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Background Hepatitis B virus (HBV) infection is difficult to cure. HBV-specific immune tolerance plays a key role in HBV persistence, and enhancing cellular and humoral immunity will improve the control of HBV infection. The purpose of the study was to explore the anti-HBV and immunostimulatory effects of msiRNAs that introduce unpaired uridine bulges in the passenger strand. Methods msiRNAs targeting the HBV S and X genes were designed and named msiHBs and msiHBx, respectively. HepG2 cells were cotransfected with siRNA or msiRNA and the HBV replication-competent plasmid pHY106-wta or pHY106-X15. HepG2.215 cells were transfected with siRNA or msiRNA. The levels of HBsAg, HBeAg, and the cytokines TNF-α, IFN-α, IFN-β, IL-1α, and IL-6 in the culture supernatant was detected by ELISA. The levels of intracellular HBV RNA, nuclear HBV replication intermediates, and HBV DNA in the supernatant were measured by quantitative RT-PCR and PCR. The levels of HBV replication intermediates were detected by Southern blotting. Peripheral blood mononuclear cells were transfected with siRNA or msiRNA, and the levels of secreted cytokines IFN-α and IFN-β were detected by ELISA. The bioactivity of type I interferons in the supernatants was detected by the virus protection assay. Results msiHBx treatment led to a significant decrease in HBsAg (to a negative level) and HBV DNA (95.5%) in the supernatant and intrahepatocellular HBV replication intermediates (89.8%) in HepG2 cells with transient HBV replication and in HepG2.2.15 cells. There was no significant difference between msiHBx and siHBx in terms of the reduction in HBV proteins and HBV replication (P > 0.05). Compared with siHBx, msiHBx treatment of HepG2 cells transfected with the HBV replication-competent plasmid led to a significant increase in the levels of the antiviral cytokines TNF-α (3.3-fold), IFN-α (1.4-fold), and IFN-β (2.5-fold) (P < 0.01), without upregulation of the proinflammatory cytokines IL-1α and IL-6. The virus protection assay results showed msiHBx-mediated type I interferons effectively protected L929 cells against ECMV infection. Conclusions msiHBx could effectively inhibit HBV expression and replication and induce an antiviral innate immune response without proinflammatory activation. The dual RNAi and immunostimulatory activity of msiRNAs may play an important role in the control of HBV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunostimulatory siRNA with a uridine bulge leads to potent inhibition of HBV and activation of innate immunity

Lan

Wei

et al. 2021

Virol J

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“…Phase I/II HBsAg reduction in HBeAg-positive and HBeAg-negative patients. Majority of patients achieved HBsAg <100 IU/mL (69) AB-729 (Arbutus) Preclinical Activity in vitro and strong HBsAg reduction in mice (115) ALN-HBV (Alnylam) Preclinical Profound and durable HBsAg silencing in vitro and in vivo (116) Targeting the viral RNA post-transcriptional regulatory element…”

Section: Targeting Covalently Closed Circular (Ccc) Dna and Its Transmentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

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Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic hepatitis B virus (HBV) treatment endpoints to guide clinical trials aiming to “cure” HBV. Agreement among the conference participants was reached on some key points. “Functional” but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post‐treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg‐positive or negative chronic hepatitis, who are treatment‐naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV “functional cure”, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

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“…The ligand interacts with the asialo-glycoprotein receptor which is highly expressed on hepatocytes. The first data on this novel siRNA approach were reported during the EASL ILC 2018 [ 46 ]. Agent AB-729 has shown promising results in a Phase 1a/1b clinical trial, as it targets all four ORFs of HBV.…”

Section: Direct Acting Antiviralsmentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

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The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

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Durable inhibition of hepatitis B virus replication and antigenemia using a subcutaneously administered siRNA agent in preclinical models

Cited by 9 publications

References 0 publications

Immunostimulatory siRNA with a uridine bulge leads to potent inhibition of HBV and activation of innate immunity

Immunostimulatory siRNA with a uridine bulge leads to potent inhibition of HBV and activation of innate immunity

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

New Approaches to the Treatment of Chronic Hepatitis B

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