title: In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides.
abstract: OBJECTIVE
  Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis of CHB. Here we evaluated the efficacy of an antisense approach using antisense oligonucleotide (ASO) technology already in clinical use for liver targeted therapy to specifically inhibit HBsAg production and viremia in a preclinical setting.
  
  
  METHODS
  A lead ASO was identified and characterized in vitro and subsequently tested for efficacy in vivo and in vitro using HBV transgenic and hydrodynamic transfection mouse and a cell culture HBV infection model, respectively.
  
  
  RESULTS
  ASO treatment decreased serum HBsAg levels ⩾2 logs in a dose and time-dependent manner; HBsAg decreased 2 logs in a week and returned to baseline 4 weeks after a single ASO injection. ASO treatment effectively reduced HBsAg in combination with entecavir, while the nucleoside analogue alone did not. ASO treatment has pan-genotypic antiviral activity in the hydrodynamic transfection system. Finally, cccDNA-driven HBV gene expression is ASO sensitive in HBV infected cells in vitro.
  
  
  CONCLUSIONS
  Our results demonstrate in a preclinical setting the efficacy of an antisense approach against HBV by efficiently reducing serum HBsAg (as well as viremia) across different genotypes alone or in combination with standard nucleoside therapy. Since the applied antisense technology is already in clinical use, a lead compound can be rapidly validated in a clinical setting and thus, constitutes a novel therapeutic approach targeting chronic HBV infection.
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Billioud
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kruse
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Carrillo
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Whitten-Bauer
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA, USA.
authors.forename: Dacao
authors.initials: D
authors.lastname: Gao
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA, USA.
authors.forename: Aneeza
authors.initials: A
authors.lastname: Kim
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Chen
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCaleb
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crosby
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Urtzi
authors.initials: U
authors.lastname: Garaigorta
authors.affiliation: Ionis Pharmaceuticals Inc., Carlsbad, CA, USA. Electronic address: eswayze@ionisph.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Swayze
authors.affiliation: Baylor College of Medicine, Houston, TX, USA. Electronic address: bissig@bcm.edu.
authors.forename: Karl-Dimiter
authors.initials: KD
authors.lastname: Bissig
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA. Electronic address: swieland@scripps.edu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieland
mesh_terms: D000818:Animals; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D006513:Hepatitis B e Antigens / Q000097:blood; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D014766:Viremia / Q000188:drug therapy*
chemical_list: D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D016376:Oligonucleotides, Antisense
keywords: 2′MOE antisense molecule; HBV Infection; HBV transgenic mice; Hydrodynamic transfection