In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides

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• 作者：Gaetan Billioud¹ ; Robert L. Kruse⁴ ; Melissa Carrillo¹ ; Christina Whitten-Bauer¹ ; Dacao Gao² ; Aneeza Kim² ; Leon Chen⁴ ; Michael L. McCaleb² ; Jeffrey R. Crosby² ; Robert Hamatake³ ; Zhi Hong³ ; Urtzi Garaigorta¹ ; Eric Swayze² ; ^{eswayze@ionisph.com" class="auth_mail" title="E-mail the corresponding author} ; Karl-Dimiter Bissig⁴ ; ^{bissig@bcm.edu" class="auth_mail" title="E-mail the corresponding author} ; Stefan Wieland¹ ; ^{swieland@scripps.edu" class="auth_mail" title="E-mail the corresponding author} ; ^{stefan.wieland@unibas.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HBV ; hepatitis B virus ; ASO ; antisense oligonucleotide ; HBsAg ; hepatitis B surface antigen ; HCC ; hepatocellular carcinoma ; NTCP ; sodium taurocholate cotransporting polypeptide ; cccDNA ; circular covalently closed DNA ; RT ; reverse transcriptase ; HBcAg ; hepatitis B core antigen ; NUC ; nucleos(t)ide analogue ; RNAi ; RNA interference ; MOE ; methoxy-ethyl ; HBeAg ; hepatitis B e antigen ; GAPDH ; Glyceraldehyde 3-phosphate dehydrogenase ; g.e. ; genome equivalent ; ISG ; interferon-stimulated gene ; ETV ; entecavi
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：64
• 期：4
• 页码：781-789
• 全文大小：1160 K

文摘

Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis of CHB. Here we evaluated the efficacy of an antisense approach using antisense oligonucleotide (ASO) technology already in clinical use for liver targeted therapy to specifically inhibit HBsAg production and viremia in a preclinical setting.

Methods

A lead ASO was identified and characterized in vitro and subsequently tested for efficacy in vivo and in vitro using HBV transgenic and hydrodynamic transfection mouse and a cell culture HBV infection model, respectively.

Results

ASO treatment decreased serum HBsAg levels ⩾2 logs in a dose and time-dependent manner; HBsAg decreased 2 logs in a week and returned to baseline 4 weeks after a single ASO injection. ASO treatment effectively reduced HBsAg in combination with entecavir, while the nucleoside analogue alone did not. ASO treatment has pan-genotypic antiviral activity in the hydrodynamic transfection system. Finally, cccDNA-driven HBV gene expression is ASO sensitive in HBV infected cells in vitro.

Conclusion

Our results demonstrate in a preclinical setting the efficacy of an antisense approach against HBV by efficiently reducing serum HBsAg (as well as viremia) across different genotypes alone or in combination with standard nucleoside therapy. Since the applied antisense technology is already in clinical use, a lead compound can be rapidly validated in a clinical setting and thus, constitutes a novel therapeutic approach targeting chronic HBV infection.