P0542 : Therapeutic effect against hepatitis B of various nucleic acid polymers in the chronic DHBV infection model

Brikh, Celia; Jamard, Catherine; Quinet, J.; Bouchareb, C.; Roehl, Ingo; Vaillant, Andrew; Cova, Lucyna

doi:10.1016/s0168-8278(15)30749-2

Cited by 2 publications

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“…Tissue accumulation in the liver exceeds 50 μM only at the 6 month time point for REP 2139 and remains less than 10 μM at the end of 6 months of dosing with REP 2165. These results replicate those observed for liver accumulation in preclinical studies 25 and are consistent with the known pharmacokinetic and tissue distribution behaviours common to all phosphorothioate oligonucleotides 22 26 27 . Based on the chemical modifications present in REP 2006 and REP 2055 their intermediate stability relative to REP 2139 and REP 2165 25 will result in liver accumulation for these NAPs within the limits observed for REP 2139 and REP 2165 but will have the same rapid clearance characteristics from the plasma.…”

Section: Discussionsupporting

confidence: 86%

“…These results replicate those observed for liver accumulation in preclinical studies 25 and are consistent with the known pharmacokinetic and tissue distribution behaviours common to all phosphorothioate oligonucleotides 22 26 27 . Based on the chemical modifications present in REP 2006 and REP 2055 their intermediate stability relative to REP 2139 and REP 2165 25 will result in liver accumulation for these NAPs within the limits observed for REP 2139 and REP 2165 but will have the same rapid clearance characteristics from the plasma. In all clinical assessments of REP 2055, REP 2139 and REP 2165 performed to date, substantial HBsAg reductions and or clearance is achieved well within 3 months 5 28 29 well before any immunostimulatory or pro-inflammatory activity would be predicted to occur based on pharmacokinetics in non-human primates and the weak pro-inflammatory and immunostimulatory properties of NAPs observed in this study.…”

Section: Discussionsupporting

confidence: 86%

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Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Real

Werner

Paul

et al. 2017

Sci Rep

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Nucleic acid polymers (NAPs) block the release of subviral particles from hepatocytes, a mechanism consistent with their antiviral activity against hepatitis B virus (HBV) in patients. Analysis of immunostimulatory properties of NAPs were conducted with several NAP species: REP 2006, the prototypic degenerate NAP [dN]40, containing TLR9-stimulatory CpG; REP 2055 a clinically active NAP with a sequence [dAdC]20 devoid of CpG content; REP 2139 (also clinically active) and REP 2165 (REP 2055 analogues further rendered immunologically inactive by replacing cytidine with 5-methylcytidine and incorporating 2′-O methylation of riboses). These analyses revealed pro-inflammatory responses in human peripheral blood mononuclear cells with REP 2006 and with REP 2139 and REP 2165 only at high dose but displayed no significant antiviral activity. In primary isolated human hepatocytes and liver sinusoidal endothelial cells no significant inflammatory or antiviral responses were detected for any NAPs. In human Kupffer cells pro-inflammatory activity was observed with REP 2006 and REP 2055, whereas a weak but significant induction of interferon genes was only observed with REP 2006 at the highest concentration. We therefore hypothesize that the antiviral activity of NAPs optimized to treat HBV infection in patients cannot be explained by direct induction of innate antiviral responses.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Real

Werner

Paul

et al. 2017

Sci Rep

View full text Add to dashboard Cite

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Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection

Vaillant¹

2016

Antiviral Research

112

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Antiviral polymers are a well-studied class of broad spectrum viral attachment/entry inhibitors whose activity increases with polymer length and with increased amphipathic (hydrophobic) character. The newest members of this class of compounds are nucleic acid polymers whose activity is derived from the sequence independent properties of phosphorothioated oligonucleotides as amphipathic polymers. Although the antiviral mechanisms and broad spectrum antiviral activity of nucleic acid polymers mirror the functionality of other members of this class, they exert in addition a unique post entry activity in hepatitis B infection which inhibits the release of HBsAg from infected hepatocytes. This review provides a general overview of the antiviral polymer class with a focus on nucleic acid polymers and their development as therapeutic agents for the treatment of hepatitis B/hepatitis D. This article forms part of a symposium in Antiviral Research on ''An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.''.

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P0542 : Therapeutic effect against hepatitis B of various nucleic acid polymers in the chronic DHBV infection model

Cited by 2 publications

References 0 publications

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Nucleic acid-based polymers effective against hepatitis B Virus infection in patients don’t harbor immunostimulatory properties in primary isolated liver cells

Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection

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