title: Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I.
abstract: OBJECTIVE
  Current hepatitis B virus (HBV) management is challenging as treatment with nucleos(t)ide analogues needs to be maintained indefinitely and because interferon (IFN)-α therapy is associated with considerable toxicity. Previously, we showed that linking IFNα to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory activities which lacks the hematological toxicity of IFNα.
  
  
  METHODS
  Here, we analyse the antiviral potential of an adeno-associated vector encoding IFNα fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα (AAV-IFN) in two animal models of chronic hepadnavirus infection.
  
  
  RESULTS
  In HBV transgenic mice, we found that both vectors induced marked reductions in serum and liver HBV DNA and in hepatic HBV RNA but AAV-IFN caused lethal pancytopenia. Woodchucks with chronic hepatitis virus (WHV) infection that were treated by intrahepatic injection of vectors encoding the woodchuck sequences (AAV-wIFN or AAV-wIA), experienced only a slight reduction of viremia which was associated with hematological toxicity and high mortality when using AAV-wIFN, while AAV-wIA was well tolerated. However, when we tested AAV-wIA or a control vector encoding woodchuck apolipoprotein A-I (AAV-wApo) in combination with entecavir, we found that AAV-wApo-treated animals exhibited an immediate rebound of viral load upon entecavir withdrawal while, in AAV-wIA-treated woodchucks, viremia and antigenemia remained at low levels for several weeks following entecavir interruption.
  
  
  CONCLUSIONS
  Treatment with AAV-IA is safe and elicits antiviral effects in animal models with difficult to treat chronic hepadnavirus infection. AAV-IA in combination with nucleos(t)ide analogues represents a promising approach for the treatment of HBV infection in highly viremic patients.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain. Electronic address: pberraondol@unav.es.
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Korolowicz
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Linta M
authors.initials: LM
authors.lastname: Thampi
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Otano
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Lester
authors.initials: L
authors.lastname: Suarez
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fioravanti
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Aranda
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Ardaiz
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Junming
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Bhaskar V
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Tucker
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Vasquez
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015613:Hepadnaviridae / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000628:therapy* / Q000821:virology; D016898:Interferon-alpha / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D004279:DNA, Viral; D016898:Interferon-alpha
keywords: Antivirals; Chronic hepatitis B; Genetic transfer; IFN-α hematological toxicity; Woodchuck