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. 2018 Jan:149:26-33.
doi: 10.1016/j.antiviral.2017.10.022. Epub 2017 Nov 8.

Activity of nucleic acid polymers in rodent models of HBV infection

Katrin Schöneweis  1 , Neil Motter  2 , Pia L Roppert  3 , Mengji Lu  1 , Baoju Wang  4 , Ingo Roehl  5 , Dieter Glebe  3 , Dongliang Yang  4 , John D Morrey  2 , Michael Roggendorf  6 , Andrew Vaillant  7
Affiliations

Activity of nucleic acid polymers in rodent models of HBV infection

Katrin Schöneweis et al. Antiviral Res. 2018 Jan.

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.

Keywords: HBV; HBsAg; Mouse; Nucleic acid polymer; Woodchuck.

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Figures

Figure 1
Figure 1
Biodostribution of REP 2139 in serum, liver and kidney of woodchucks, 24 hours after a bolus s.c. injection of 10mg/kg of REP 2139-Ca. Plotted values are mean ± standard deviation (n=3).
Figure 2
Figure 2
Antiviral effects of REP 2055 and REP 2139 in woodchucks with chronic WHV infection (n=4). Experimental design is indicated in (A). Changes during treatment in serum WHsAg (B), WHV DNA (C) and AST (D) are presented. BL = baseline.
Figure 3
Figure 3
Antiviral effects of REP 2139-Ca in woodchucks with chronic WHV infection (n=6). Experimental design is indicated in (A). Changes during treatment in serum WHsAg (B), WHV DNA (C) and AST (D) are presented. BL = baseline
Figure 4
Figure 4
Antiviral effects of entecavir, REP 2055 and REP 2031 in HBV infected SCID-Hu mice. Changes in body weight (A), serum human albumin (B), HBsAg (C), HBeAg (D) and HBV DNA (E) are presented. Plotted values are mean ± standard deviation (n=5).
Figure 5
Figure 5
Antiviral effects of REP 2139-Ca in HBV transgenic mice. A) changes in serum HBsAg levels in “Chisari” (top) and “PAMF” (bottom) HBV transgenic mice during two weeks of treatment with REP 2139-Ca. B) changes in serum HBsAg levels in PAMF HBV transgenic mice during 12 weeks of treatment with REP 2139-Ca. Arrows indicate treatment days. Plotted values are mean ± standard deviation (n=6 [Chisari] and n=7 [PAMF] in (A), n=11 in (B)).
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