Activity of nucleic acid polymers in rodent models of HBV infection.

Abstract

Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs). The clinically active NAP species REP 2055 and REP 2139 were investigated in other relevant animal models of HBV infection including woodchucks chronically infected with WHV, HBV transgenic mice and HBV infected SCID-Hu mice. The liver accumulation of REP 2139 in woodchucks following subcutaneous administration was examined and was found to be similar to that observed in mice and ducks. However, in woodchucks, NAP treatment was associated with only mild (36-79% relative to baseline) reductions in WHsAg (4/10 animals) after 3-5 weeks of treatment without changes in serum WHV DNA. In HBV infected SCID-Hu mice, REP 2055 treatment was not associated with any reduction of HBsAg, HBeAg or HBV DNA in the serum after 28 days of treatment. In HBV transgenic mice, no reductions in serum HBsAg were observed with REP 2139 with up to 12 weeks of treatment. In conclusion, the antiviral effects of NAPs in DHBV infected ducks and patients with chronic HBV infection were weak or absent in woodchuck and mouse models despite similar liver accumulation of NAPs in all these species, suggesting that the mechanisms of SVP assembly and or secretion present in rodent models differs from that in DHBV and chronic HBV infections.

• Authors: Katrin Schöneweis, Neil Motter, Pia L Roppert, Mengji Lu, Baoju Wang, Ingo Roehl, Dieter Glebe, Dongliang Yang, John D Morrey, Michael Roggendorf, Andrew Vaillant
• Journal: Antiviral research (Antiviral Res) Vol. 149 Pg. 26-33 (01 2018) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 29126900 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Hepatitis B Surface Antigens
• Nucleic Acids
• Polymers

Topics

• Animals
• Biomarkers
• Disease Models, Animal
• Hepatitis B (blood, drug therapy, virology)
• Hepatitis B Surface Antigens (blood)
• Hepatitis B Virus, Woodchuck (drug effects)
• Hepatitis B virus (drug effects)
• Humans
• Marmota
• Mice
• Mice, Transgenic
• Nucleic Acids (chemistry, pharmacology)
• Polymers (chemistry)
• Rodentia
• Virus Replication (drug effects)