Aiming for cure in HBV and HDV infection

Petersen, J.; Thompson, Alexander; Levrero, Massimo

doi:10.1016/j.jhep.2016.05.043

Cited by 67 publications

(49 citation statements)

References 114 publications

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“…Except for the above projects, Fitusiran (ALN-AT3) (K.J., Pasi et al., 2016, Haemophilia, abstract)71, 72 (targeting antithrombin for the treatment of hemophilia and rare bleeding disorders), ALN-PCSsc (K. Fitzgerald et al., 2015, Circulation, abstract)73, 74 (targeting proprotein convertase subtilisin/kexin type 9 for the treatment of hypercholesterolemia), ALN-CC5 75 (targeting complement component 5 for the treatment of complement-mediated diseases), ALN-GO176, 77 (targeting glycolate oxidase for the treatment of primary hyperoxaluria type 1), and ALN-HBV (L. Sepp-Lorenzino et al., 2015, Hepatology, abstract)78, 79 (targeting the hepatitis B virus [HBV] genome for the treatment of HBV infection) are undergoing phase II or phase I/II clinical trial. ALN-AS180, 81 (targeting aminolevulinic acid synthase 1 for the treatment of acute hepatic porphyrias) is in phase I clinical study.…”

Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang

2017

Molecular Therapy - Nucleic Acids

241

203

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A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.

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Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang

2017

Molecular Therapy - Nucleic Acids

241

203

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“…lamivudine, adefovir, entecavir), which potently inhibit the HBV reverse transcriptase and are approved antiviral drugs for the treatment of chronic HBV infection, do not show beneficial effects in chronically HBV/HDV co-infected patients 2 . To date, no HDV-specific therapy is available or has been approved 3 . Thus, treatment options for chronically HBV/HDV co-infected patients are limited to interferons and pegylated interferon alpha (peg-IFNα) is the only currently approved treatment.…”

Section: Introductionmentioning

confidence: 99%

Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice

Giersch

Homs

Volz

et al. 2017

Sci Rep

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Co-infection with hepatitis B (HBV) and D virus (HDV) is associated with the most severe course of liver disease. Interferon represents the only treatment currently approved. However, knowledge about the impact of interferons on HDV in human hepatocytes is scant. Aim was to assess the effect of pegylated interferon alpha (peg-IFNα) and lambda (peg-IFNλ), compared to the HBV-polymerase inhibitor entecavir (ETV) on all HDV infection markers using human liver chimeric mice and novel HDV strand-specific qRT-PCR and RNA in situ hybridization assays, which enable intrahepatic detection of HDV RNA species. Peg-IFNα and peg-IFNλ reduced HDV viremia (1.4 log and 1.2 log, respectively) and serum HBsAg levels (0.9-log and 0.4-log, respectively). Intrahepatic quantification of genomic and antigenomic HDV RNAs revealed a median ratio of 22:1 in untreated mice, resembling levels determined in HBV/HDV infected patients. Both IFNs greatly reduced intrahepatic levels of genomic and antigenomic HDV RNA, increasing the amounts of HDAg- and antigenomic RNA-negative hepatocytes. ETV-mediated suppression of HBV replication (2.1-log) did not significantly affect HBsAg levels, HDV productivity and/or release. In humanized mice lacking adaptive immunity, IFNs but not ETV suppressed HDV. Viremia decrease reflected the intrahepatic reduction of all HDV markers, including the antigenomic template, suggesting that intracellular HDV clearance is achievable.

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“…However, the details of the host-virus interactions such as autophagy worth to be further clarified. To investigate the complex network of interactions with the host in the course of HBV infection is helpful to define new targets for antiviral strategies [6]. …”

Section: Introductionmentioning

confidence: 99%

MicroRNA-141 Targets Sirt1 and Inhibits Autophagy to Reduce HBV Replication

Yang¹,

Liu²,

Xue³

et al. 2017

Cell Physiol Biochem

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Background/Aims: About 400 million individuals are chronically infected with hepatitis B virus, at high risk of developing liver cirrhosis and hepatocellular carcinoma. Recent studies have demonstrated an interaction between hepatitis B virus replication and autophagy activity of hepatocytes. In the present study, we aimed to investigate the role of miR-141 in regulating autophagy and hepatitis B virus replication. Methods: The expression of HBV-DNA, miR-141 and Sirt1 mRNA was determined by quantitative real-time PCR analysis. The expression of HBsAg and HBeAg was determined by ELISA. Western blotting was performed to detect protein expression. The LC3 puncta was determined by immunofluorescence. To test whether miR-141 directly regulate the expression level of Sirt1 mRNA, dual-luciferase reporter gene assay was performed. Results: In vitro studies showed that miR-141 mimic inhibited the autophagic response, hepatitis B virus and the expression of Sirt1 in hepatocytes. And transfection with miR-141 inhibitor enhanced autophagic response and Sirt1 expression. The autophagy induced by overexpression of Sirt1 was inhibited by miR-141 mimic. In addition, miR-141 mimic also decreased the expression of Sirt1 mRNA. Sirt1 was predicted as a potential miR-141 target by bioinformatic analysis of its 3'-UTR, and confirmed by luciferase reporter assays which analyzing the interaction of miR-141 with the wild- type or the mutated Sirt1 3’-UTR. Conclusion: We have therefore demonstrated a role of miR-141 in regulating autophagy-mediated hepatitis B virus inhibition by targeting Sirt1, and may provide potential targets for drug development.

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Aiming for cure in HBV and HDV infection

Cited by 67 publications

References 114 publications

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice

MicroRNA-141 Targets Sirt1 and Inhibits Autophagy to Reduce HBV Replication

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