Liver-directed gene therapy of chronic hepadnavirus infection using interferon alpha tethered to apolipoprotein A-I

J Hepatol. 2015 Aug;63(2):329-36. doi: 10.1016/j.jhep.2015.02.048. Epub 2015 Mar 12.

Abstract

Background & aims: 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.

Keywords: Antivirals; Chronic hepatitis B; Genetic transfer; IFN-α hematological toxicity; Woodchuck.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Apolipoprotein A-I / metabolism*
  • DNA, Viral / genetics*
  • Disease Models, Animal
  • Female
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Hepadnaviridae / genetics*
  • Hepatitis B, Chronic / genetics
  • Hepatitis B, Chronic / therapy*
  • Hepatitis B, Chronic / virology
  • Interferon-alpha / therapeutic use*
  • Liver / drug effects*
  • Liver / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic

Substances

  • Antiviral Agents
  • Apolipoprotein A-I
  • DNA, Viral
  • Interferon-alpha