{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:17:54Z","timestamp":1792642674206,"version":"4.5.0"},"reference-count":151,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T00:00:00Z","timestamp":1663286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/v14092052","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:08:09Z","timestamp":1663718889000},"page":"2052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1433-0700","authenticated-orcid":false,"given":"Andrew","family":"Vaillant","sequence":"first","affiliation":[{"name":"Replicor Inc., 6100 Royalmount Avenue, Montreal, QC H4P 2R2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41573-021-00162-z","article-title":"Antisense technology: An overview and prospectus","volume":"20","author":"Crooke","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7108","DOI":"10.1074\/jbc.M210326200","article-title":"Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis","volume":"278","author":"Vickers","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/intimm\/dxp017","article-title":"The roles of TLRs, RLRs and NLRs in pathogen recognition","volume":"21","author":"Kawai","year":"2009","journal-title":"Int. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1089\/oli.2009.0180","article-title":"siRNA and innate immunity","volume":"19","author":"Robbins","year":"2009","journal-title":"Oligonucleotides"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1146\/annurev.immunol.20.100301.064842","article-title":"CpG motifs in bacterial DNA and their immune effects","volume":"20","author":"Krieg","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nbt1081","article-title":"Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA","volume":"23","author":"Judge","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.jmb.2005.03.013","article-title":"Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization","volume":"348","author":"Sioud","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nm1191","article-title":"Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7","volume":"11","author":"Hornung","year":"2005","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-3-540-72167-3_4","article-title":"RNA recognition via TLR7 and TLR8","volume":"183","author":"Hornung","year":"2008","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"0076","DOI":"10.1038\/s41570-017-0076","article-title":"Analysis of aptamer discovery and technology","volume":"1","author":"Dunn","year":"2017","journal-title":"Nat. Rev. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5235","DOI":"10.1093\/nar\/gkaa299","article-title":"Phosphorothioate modified oligonucleotide-protein interactions","volume":"48","author":"Crooke","year":"2020","journal-title":"Nucl. Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.antiviral.2016.07.004","article-title":"Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection","volume":"133","author":"Vaillant","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1021\/acsinfecdis.8b00156","article-title":"REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection","volume":"5","author":"Vaillant","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1128\/AAC.50.4.1393-1401.2006","article-title":"Phosphorothioate oligonucleotides inhibit human immunodeficiency virus type 1 fusion by blocking gp41 core formation","volume":"50","author":"Vaillant","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.virol.2007.10.016","article-title":"Inhibition of cellular entry of lymphocytic choriomeningitis virus by amphipathic DNA polymers","volume":"372","author":"Lee","year":"2008","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1128\/AAC.50.3.1034-1044.2006","article-title":"Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides","volume":"50","author":"Kocisko","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","first-page":"504A","article-title":"Interaction of nucleic acid polymers with the large and small forms of hepatitis delta antigen protein","volume":"66","author":"Shamur","year":"2017","journal-title":"Hepatology"},{"key":"ref_18","first-page":"512A","article-title":"PH-dependent Interaction of NAPs with the HSP40 Chaperone DnaJB12","volume":"74","author":"Boulon","year":"2021","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1021\/ja00718a039","article-title":"Nucleoside phosphorothioates","volume":"92","author":"Eckstein","year":"1970","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11691","DOI":"10.1093\/nar\/16.24.11691","article-title":"Inhibition of deoxyribonucleases by phosphorothioate groups in oligodeoxyribonucleotides","volume":"16","author":"Spitzer","year":"1988","journal-title":"Nucl. Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/oli.1.2000.10.117","article-title":"Phosphorothioate oligodeoxynucleotides: What is their origin and what is unique about them?","volume":"10","author":"Eckstein","year":"2000","journal-title":"Antisense Nucl. Acid Drug Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1093\/nar\/24.16.3261","article-title":"Hydration of single-stranded phosphodiester and phosphorothioate oligodeoxyribonucleotides","volume":"24","author":"White","year":"1996","journal-title":"Nucl. Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/nar\/24.5.829","article-title":"NMR investigations of duplex stability of phosphorothioate and phosphorodithioate DNA analogues modified in both strands","volume":"24","author":"Jaroszewski","year":"1996","journal-title":"Nucl. Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.bbrc.2007.06.177","article-title":"Suppression of immunostimulatory siRNA-driven innate immune activation by 2\u2019-modified RNAs","volume":"361","author":"Sioud","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ymthe.2005.11.002","article-title":"Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo","volume":"13","author":"Judge","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0005-2736(00)00151-6","article-title":"Interaction of oligonucleotides with cationic lipids: The relationship between electrostatics, hydration and state of aggregation","volume":"1464","author":"Meidan","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1146\/annurev.biophys.36.040306.132556","article-title":"Insights from crystallographic studies into the structural and pairing properties of nucleic acid analogs and chemically modified DNA and RNA oligonucleotides","volume":"36","author":"Egli","year":"2007","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9645","DOI":"10.1021\/acs.jmedchem.6b00551","article-title":"The Medicinal Chemistry of Therapeutic Oligonucleotides","volume":"59","author":"Wan","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/s41587-019-0106-2","article-title":"Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index","volume":"37","author":"Shen","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6078","DOI":"10.1038\/s41598-019-42523-0","article-title":"Systematic evaluation of 2\u2019-Fluoro modified chimeric antisense oligonucleotide-mediated exon skipping in vitro","volume":"9","author":"Chen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14514","DOI":"10.1016\/S0021-9258(19)85268-7","article-title":"Evaluation of 2\u2019-modified oligonucleotides containing 2\u2019-deoxy gaps as antisense inhibitors of gene expression","volume":"268","author":"Monia","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/0968-0896(96)00160-5","article-title":"Hybrid oligonucleotides: Synthesis, biophysical properties, stability studies, and biological activity","volume":"4","author":"Yu","year":"1996","journal-title":"Bioorg. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1074\/jbc.274.3.1715","article-title":"Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression","volume":"274","author":"McKay","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12365","DOI":"10.1093\/nar\/gkaa928","article-title":"2\u2019-O-Methylation can increase the abundance and lifetime of alternative RNA conformational states","volume":"48","author":"Rangadurai","year":"2020","journal-title":"Nucl. Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/sj.embor.7400637","article-title":"Cleavage of the siRNA passenger strand during RISC assembly in human cells","volume":"7","author":"Leuschner","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7347","DOI":"10.1021\/bi060307w","article-title":"Thermodynamic, counterion, and hydration effects for the incorporation of locked nucleic acid nucleotides into DNA duplexes","volume":"45","author":"Kaur","year":"2006","journal-title":"Biochemistry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1093\/nar\/gkm1182","article-title":"Insights into structure, dynamics and hydration of locked nucleic acid (LNA) strand-based duplexes from molecular dynamics simulations","volume":"36","author":"Pande","year":"2008","journal-title":"Nucl. Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1021\/bi9002056","article-title":"Contributions of stacking, preorganization, and hydrogen bonding to the thermodynamic stability of duplexes between RNA and 2\u2019-O-methyl RNA with locked nucleic acids","volume":"48","author":"Kierzek","year":"2009","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.omtn.2017.05.011","article-title":"Electronic Structures of LNA Phosphorothioate Oligonucleotides","volume":"8","author":"Bohr","year":"2017","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6850","DOI":"10.1039\/C8CC09648A","article-title":"Enhancement of exon skipping activity by reduction in the secondary structure content of LNA-based splice-switching oligonucleotides","volume":"55","author":"Shimo","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1074\/jbc.M510369200","article-title":"Examining Ty3 polypurine tract structure and function by nucleoside analog interference","volume":"281","author":"Dash","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11043","DOI":"10.1038\/s41598-017-09147-8","article-title":"LNA effects on DNA binding and conformation: From single strand to duplex and triplex structures","volume":"7","author":"Xu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Xu, Y., Gissberg, O., Pabon-Martinez, Y.V., Wengel, J., Lundin, K.E., Smith, C.I.E., Zain, R., Nilsson, L., and Villa, A. (2019). The ability of locked nucleic acid oligonucleotides to pre-structure the double helix: A molecular simulation and binding study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211651"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1093\/nar\/gkv1210","article-title":"Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts","volume":"44","author":"Burel","year":"2016","journal-title":"Nucl. Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"30377","DOI":"10.1038\/srep30377","article-title":"Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides","volume":"6","author":"Kasuya","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Freitas-Lopes, M.A., Mafra, K., David, B.A., Carvalho-Gontijo, R., and Menezes, G.B. (2017). Differential Location and Distribution of Hepatic Immune Cells. Cells, 6.","DOI":"10.3390\/cells6040048"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1159\/000489966","article-title":"Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines","volume":"10","author":"Vegna","year":"2018","journal-title":"J. Innate Immun."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Werner, M., Schefczyk, S., Trippler, M., Treckmann, J.W., Baba, H.A., Gerken, G., Schlaak, J.F., and Broering, R. (2022). Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses, 14.","DOI":"10.3390\/v14020218"},{"key":"ref_49","first-page":"420","article-title":"Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice","volume":"281","author":"Raynaud","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1124\/dmd.31.11.1419","article-title":"Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2\u2019-O-(2-methoxyethyl) modified antisense oligonucleotide: Comparison across species","volume":"31","author":"Geary","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1124\/dmd.106.012401","article-title":"Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100","volume":"35","author":"Yu","year":"2007","journal-title":"Drug Metab. Dispos."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtn.2017.04.019","article-title":"Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy","volume":"8","author":"Roehl","year":"2017","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1093\/nar\/25.16.3290","article-title":"In vivo fate of phosphorothioate antisense oligodeoxynucleotides: Predominant uptake by scavenger receptors on endothelial liver cells","volume":"25","author":"Bijsterbosch","year":"1997","journal-title":"Nucl. Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/mt.2010.85","article-title":"Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms","volume":"18","author":"Akinc","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1369\/0022155411410885","article-title":"Biodistribution of small interfering RNA at the organ and cellular levels after lipid nanoparticle-mediated delivery","volume":"59","author":"Shi","year":"2011","journal-title":"J. Histochem. Cytochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1073\/pnas.1322937111","article-title":"Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates","volume":"111","author":"Dong","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e210","DOI":"10.1038\/mtna.2014.61","article-title":"Shielding of Lipid Nanoparticles for siRNA Delivery: Impact on Physicochemical Properties, Cytokine Induction, and Efficacy","volume":"3","author":"Kumar","year":"2014","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.ymthe.2020.06.015","article-title":"Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug","volume":"28","author":"Debacker","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8796","DOI":"10.1093\/nar\/gku531","article-title":"Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice","volume":"42","author":"Prakash","year":"2014","journal-title":"Nucl. Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1177\/0192623318792537","article-title":"The Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies","volume":"46","author":"Janas","year":"2018","journal-title":"Toxicol. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1208760","article-title":"Safety and efficacy of RNAi therapy for transthyretin amyloidosis","volume":"369","author":"Coelho","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0140-6736(13)61914-5","article-title":"Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin\/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial","volume":"383","author":"Fitzgerald","year":"2014","journal-title":"Lancet"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1056\/NEJMoa1701329","article-title":"Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides","volume":"377","author":"Graham","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1609243","article-title":"A Highly Durable RNAi Therapeutic Inhibitor of PCSK9","volume":"376","author":"Fitzgerald","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1681\/ASN.2016030338","article-title":"An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria","volume":"28","author":"Liebow","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ymthe.2016.10.019","article-title":"Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate","volume":"25","author":"Zimmermann","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1056\/NEJMoa1807838","article-title":"Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria","volume":"380","author":"Sardh","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e135348","DOI":"10.1172\/jci.insight.135348","article-title":"Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease","volume":"5","author":"Wooddell","year":"2020","journal-title":"JCI Insight"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1002\/ehf2.13154","article-title":"Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: Preclinical and phase 1 data","volume":"8","author":"Viney","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1124\/dmd.121.000428","article-title":"The Nonclinical Disposition and Pharmacokinetic\/Pharmacodynamic Properties of N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human","volume":"50","author":"McDougall","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1093\/eurheartj\/ehab820","article-title":"Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk","volume":"43","author":"Tardif","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13059-017-1162-x","article-title":"RNAs competing for microRNAs mutually influence their fluctuations in a highly non-linear microRNA-dependent manner in single cells","volume":"18","author":"Bosia","year":"2017","journal-title":"Genome Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e252","DOI":"10.1038\/mtna.2015.23","article-title":"siRNA Versus miRNA as Therapeutics for Gene Silencing","volume":"4","author":"Lam","year":"2015","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.chom.2013.09.002","article-title":"Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells","volume":"14","author":"Seo","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"11827","DOI":"10.1093\/nar\/gkaa670","article-title":"Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates","volume":"48","author":"Brown","year":"2020","journal-title":"Nucl. Acids Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.jhep.2009.05.022","article-title":"Control of cccDNA function in hepatitis B virus infection","volume":"51","author":"Levrero","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Tu, T., Budzinska, M.A., Shackel, N.A., and Urban, S. (2017). HBV DNA Integration: Molecular Mechanisms and Clinical Implications. Viruses, 9.","DOI":"10.3390\/v9040075"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.2147\/IDR.S240472","article-title":"cccDNA Maintenance in Chronic Hepatitis B\u2014Targeting the Matrix of Viral Replication","volume":"13","author":"Dandri","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1021\/acsinfecdis.0c00638","article-title":"HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection","volume":"7","author":"Vaillant","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cmi.2014.10.007","article-title":"Whole genome characterization of hepatitis B virus quasispecies with massively parallel pyrosequencing","volume":"21","author":"Li","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1128\/JCM.00068-15","article-title":"Characterization of Full-Length Genomes of Hepatitis B Virus Quasispecies in Sera of Patients at Different Phases of Infection","volume":"53","author":"Yang","year":"2015","journal-title":"J. Clin. Microbiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/hep.31240","article-title":"Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients","volume":"73","author":"Huang","year":"2021","journal-title":"Hepatology"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Liu, Y., Maya, S., and Ploss, A. (2021). Animal Models of Hepatitis B Virus Infection-Success, Challenges, and Future Directions. Viruses, 13.","DOI":"10.3390\/v13050777"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.4049\/jimmunol.172.5.2731","article-title":"Of mice and not men: Differences between mouse and human immunology","volume":"172","author":"Mestas","year":"2004","journal-title":"J. Immunol."},{"key":"ref_85","first-page":"433","article-title":"Differences in innate immune response between man and mouse","volume":"34","author":"Zschaler","year":"2014","journal-title":"Crit. Rev. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9237","DOI":"10.1073\/pnas.161293498","article-title":"Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition","volume":"98","author":"Bauer","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.ajpath.2013.12.006","article-title":"Discordant biological and toxicological species responses to TLR3 activation","volume":"184","author":"Mitchell","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7770","DOI":"10.1016\/S0021-9258(18)34448-X","article-title":"Structure of hepatitis B surface antigen. Characterization of the lipid components and their association with the viral proteins","volume":"257","author":"Gavilanes","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.antiviral.2017.10.022","article-title":"Activity of nucleic acid polymers in rodent models of HBV infection","volume":"149","author":"Schoneweis","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"180","DOI":"10.2174\/187231210791698456","article-title":"Morphologic characterization of PhoenixBio (uPA+\/+\/SCID) humanized liver chimeric mouse model","volume":"4","author":"Peterson","year":"2010","journal-title":"Drug Metab. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"43838","DOI":"10.1038\/srep43838","article-title":"Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don\u2019t harbor immunostimulatory properties in primary isolated liver cells","volume":"7","author":"Real","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.antiviral.2019.02.009","article-title":"Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15cells","volume":"164","author":"Blanchet","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"104853","DOI":"10.1016\/j.antiviral.2020.104853","article-title":"Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro","volume":"183","author":"Boulon","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S871","DOI":"10.1016\/S0168-8278(22)02037-2","article-title":"Safety, pharmacokinetics, and antiviral activity of the S-antigen Transport Inhibiting Oligonucleotide Polymers (STOPS) drug candidate ALG-010133 in subjects with chronic hepatitis B","volume":"77","author":"Gane","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.omtn.2022.03.002","article-title":"Editorial: In vitro mechanistic evaluation of nucleic acid polymers: A cautionary tale","volume":"28","author":"Vaillant","year":"2022","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.omtn.2021.12.013","article-title":"Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules","volume":"27","author":"Kao","year":"2021","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Noordeen, F., Scougall, C.A., Grosse, A., Qiao, Q., Ajilian, B.B., Reaiche-Miller, G., Finnie, J., Werner, M., Broering, R., and Schlaak, J.F. (2015). Therapeutic Antiviral Effect of the Nucleic Acid Polymer REP 2055 against Persistent Duck Hepatitis B Virus Infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140909"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5291","DOI":"10.1128\/AAC.01003-13","article-title":"Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro","volume":"57","author":"Noordeen","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5299","DOI":"10.1128\/AAC.01005-13","article-title":"Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo","volume":"57","author":"Noordeen","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1002\/hep.29737","article-title":"Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks","volume":"67","author":"Quinet","year":"2018","journal-title":"Hepatology"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Al-Mahtab, M., Bazinet, M., and Vaillant, A. (2016). Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156667"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1053\/j.gastro.2020.02.058","article-title":"Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy","volume":"158","author":"Bazinet","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1002\/hep4.1767","article-title":"Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy","volume":"5","author":"Bazinet","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1002\/hep4.1951","article-title":"HBsAg isoform dynamics during NAP-based therapy of HBeAg-negative chronic HBV and HBV\/HDV infection","volume":"6","author":"Bazinet","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S2468-1253(17)30288-1","article-title":"Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): A non-randomised, open-label, phase 2 trial","volume":"2","author":"Bazinet","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/hep4.1633","article-title":"Persistent control of HBV and HDV infection following REP 2139-Ca and pegIFN therapy in chronic HBV\/HDV co-infection","volume":"5","author":"Bazinet","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_107","first-page":"LP-14","article-title":"Subcutaneous administration of REP 2139-Mg in the compassionate treatment of cirrhotic HBV\/HDV co-infection","volume":"2021","author":"Bourliere","year":"2021","journal-title":"AASLD"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3849","DOI":"10.3748\/wjg.14.3849","article-title":"Combination of small interfering RNAs mediates greater suppression on hepatitis B virus cccDNA in HepG2.2.15 cells","volume":"14","author":"Xin","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.bbrc.2011.05.016","article-title":"Inhibition of hepatitis B virus (HBV) by LNA-mediated nuclear interference with HBV DNA transcription","volume":"409","author":"Sun","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Zhang, Y.L., Cheng, T., Cai, Y.J., Yuan, Q., Liu, C., Zhang, T., Xia, D.Z., Li, R.Y., Yang, L.W., and Wang, Y.B. (2010). RNA Interference inhibits hepatitis B virus of different genotypes in vitro and in vivo. BMC Microbiol., 10.","DOI":"10.1186\/1471-2180-10-214"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1099\/vir.0.004408-0","article-title":"Hepatitis B virus (HBV)-specific short hairpin RNA is capable of reducing the formation of HBV covalently closed circular (CCC) DNA but has no effect on established CCC DNA in vitro","volume":"90","author":"Starkey","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1053\/j.gastro.2004.12.007","article-title":"RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant","volume":"128","author":"Wu","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.omtn.2018.02.005","article-title":"Liver-Targeted Anti-HBV Single-Stranded Oligonucleotides with Locked Nucleic Acid Potently Reduce HBV Gene Expression In Vivo","volume":"11","author":"Javanbakht","year":"2018","journal-title":"Mol. Ther. Nucl. Acids"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/mt.2013.31","article-title":"Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection","volume":"21","author":"Wooddell","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nbt1122","article-title":"Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs","volume":"23","author":"Morrissey","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1021\/acsinfecdis.8b00191","article-title":"ARB-1740, a RNA Interference Therapeutic for Chronic Hepatitis B Infection","volume":"5","author":"Thi","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"6656","DOI":"10.1093\/nar\/gkac539","article-title":"From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization","volume":"50","author":"Schlegel","year":"2022","journal-title":"Nucl. Acids Res."},{"key":"ref_118","first-page":"267A","article-title":"Preclinical Characterization of Galxc\u2122 RNAi Therapeutics Targeting Different Regions of the HBV Genome","volume":"68","author":"Koser","year":"2018","journal-title":"Hepatology"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1002\/cbic.201500023","article-title":"Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo","volume":"16","author":"Rajeev","year":"2015","journal-title":"ChemBioChem"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/labinvest.3700629","article-title":"In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA","volume":"87","author":"Cruz","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1073\/pnas.0805434105","article-title":"Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates","volume":"105","author":"Grefhorst","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.bcp.2008.11.005","article-title":"Cross-species comparison of in vivo PK\/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100","volume":"77","author":"Yu","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1161\/CIRCRESAHA.111.300367","article-title":"Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans","volume":"112","author":"Graham","year":"2013","journal-title":"Circ. Res."},{"key":"ref_124","unstructured":"Lee, A.M. (2015, January 9). TKM-HBV RNAi Therapeutic for Chronic HBV Infeciton. Proceedings of the DIA\/FDA Oligonucleotide-Based Therapeutics Conference, Washington, DC, USA."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4161\/adna.1.1.11981","article-title":"Inhibition of hepatitis B virus replication in vivo using lipoplexes containing altritol-modified antiviral siRNAs","volume":"1","author":"Hean","year":"2010","journal-title":"Artif. DNA PNA XNA"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"10421","DOI":"10.1128\/JVI.00996-14","article-title":"Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model","volume":"88","author":"Wu","year":"2014","journal-title":"J. Virol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0166-3542(93)90051-J","article-title":"The use of ampligen alone and in combination with ganciclovir and coumermycin A1 for the treatment of ducks congenitally-infected with duck hepatitis B virus","volume":"21","author":"Niu","year":"1993","journal-title":"Antivir. Res."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Meng, Z., Zhang, X., Wu, J., Pei, R., Xu, Y., Yang, D., Roggendorf, M., and Lu, M. (2013). RNAi induces innate immunity through multiple cellular signaling pathways. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064708"},{"key":"ref_129","first-page":"22A","article-title":"HBcrAg, HBV-RNA declines in A Phase 2a Study Evaluating the Multi-dose Activity of ARB-1467 in HBeAg-Positive and Negative Virally Suppressed Subjects with Hepatitis B","volume":"66","author":"Agarwal","year":"2017","journal-title":"Hepatology"},{"key":"ref_130","first-page":"23A","article-title":"Pharmacokinetics and exploratory exposure-response of siRNAs administered monthly as ARB-001467 (ARB-1467) in a Phase 2a study in HBeAg positive and negative virally suppressed subjects with chronic hepatitis B","volume":"66","author":"Eley","year":"2017","journal-title":"Hepatology"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/cpdd.318","article-title":"Safety, Tolerability, and Pharmacokinetics of ARC-520 Injection, an RNA Interference-Based Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection, in Healthy Volunteers","volume":"6","author":"Schluep","year":"2017","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"eaan0241","DOI":"10.1126\/scitranslmed.aan0241","article-title":"RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg","volume":"9","author":"Wooddell","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/hep.31008","article-title":"RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients with Chronic Hepatitis B Infection","volume":"72","author":"Yuen","year":"2020","journal-title":"Hepatology"},{"key":"ref_134","first-page":"1","article-title":"Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB","volume":"20","author":"Yuen","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_135","first-page":"S287","article-title":"Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: Week 48 follow-up results","volume":"75","author":"Gane","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_136","unstructured":"Yuen, M.F. (2020, January 11\u201316). HBV RNAi Inhibitor RG6346 in Phase 1b-2a Trial was Safe, Well Tolerated, and Resulted in Subatantial and Durable Reductions in Serum HBsAg Levels. Presented at the AASLD 2020 Late Breakong Oral Presentation, Online."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"S876","DOI":"10.1016\/S0168-8278(22)02045-1","article-title":"Long-term suppression maintained after cessation of AB-729 treatment and comparable on-treatment response observed in HBeAg+ subjects","volume":"77","author":"Yuen","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_138","first-page":"S738","article-title":"Preliminary on-treatment data from a phase 2 study evaluating VIR-2218 in combination with pegylated interferon alfa-2a in participants with chronic hepatitis B infection","volume":"75","author":"Yuen","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1136\/gutjnl-2020-323445","article-title":"Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment","volume":"71","author":"Yuen","year":"2021","journal-title":"Gut"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"S850","DOI":"10.1016\/S0168-8278(22)01998-5","article-title":"Inhibition of hepatitis B surface antigen by RNA interference therapeutic AB-729 is associated with increased cytokine signatures in HBV DNA+ chronic hepatitis B patients","volume":"77","author":"Ganchua","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"S851","DOI":"10.1016\/S0168-8278(22)01999-7","article-title":"Reduction of hepatitis B surface antigen mediated by RNA interference therapeutic AB-729 in chronic hepatitis B patients is associated with T cell activation and a decline in exhausted CD8 T cells","volume":"77","author":"Ganchua","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jhep.2022.05.031","article-title":"Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy","volume":"77","author":"Yuen","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1002\/hep.31920","article-title":"Clinical Study of Single Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients with Chronic Hepatitis B","volume":"74","author":"Gane","year":"2021","journal-title":"Hepatology"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Vaillant, A. (2022). Targeting Subviral Particles: A Critical Step in Achieving HBV Functional Cure but Where Are We with Current Agents in Clinical Development?. Viruses, 14.","DOI":"10.3390\/v14061193"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1038\/s41591-021-01513-4","article-title":"Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: A phase 2 randomized controlled trial","volume":"27","author":"Yuen","year":"2021","journal-title":"Nat. Med."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1161\/CIRCULATIONAHA.105.606442","article-title":"Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B","volume":"114","author":"Kastelein","year":"2006","journal-title":"Circulation"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1080\/13506129.2016.1191458","article-title":"Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides","volume":"23","author":"Ackermann","year":"2016","journal-title":"Amyloid"},{"key":"ref_148","first-page":"S455","article-title":"Treatment with GSK3228836 Leads to HBsAg Reduction and Induction of Interferon Gamma Related Proteins and Chemokines in a Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study","volume":"75","author":"You","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1002\/hep.31795","article-title":"Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B","volume":"74","author":"Gane","year":"2021","journal-title":"Hepatology"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Ayithan, N., Ghosh, A., Dwivedi, A., Wallin, J.J., Tan, S.K., Chen, D., Kottilil, S., and Poonia, B. (2021). Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans. Viruses, 13.","DOI":"10.3390\/v13122400"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1089\/hum.2008.131","article-title":"Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation","volume":"19","author":"Robbins","year":"2008","journal-title":"Hum. Gene Ther."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2052\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:32:40Z","timestamp":1760142760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,16]]},"references-count":151,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["v14092052"],"URL":"https:\/\/doi.org\/10.3390\/v14092052","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,16]]}}}