Liver-Targeted Anti-HBV Single-Stranded Oligonucleotides with Locked Nucleic Acid Potently Reduce HBV Gene Expression In Vivo
| Autor: | Lykke Pedersen, Robert Persson, Corinne Ploix, Xue Zhou, John A. T. Young, Thushara Pattupara, Hassan Javanbakht, Tianlai Shi, Johanna Walther, Julie Elisabeth Françoise Blaising, Henrik Mueller, Wouter H. P. Driessen, Nanna Albæk, Jacob Ravn, Anaïs Lopez, Søren Ottosen, Malene Jackerott |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
HBsAg antisense medicine.disease_cause AAV-HBV-infected mouse model Article 03 medical and health sciences viral gene expression In vivo Drug Discovery Gene expression HBV medicine Locked nucleic acid locked nucleic acid Hepatitis B virus Chemistry Oligonucleotide lcsh:RM1-950 Virology lcsh:Therapeutics. Pharmacology 030104 developmental biology HBeAg Molecular Medicine Asialoglycoprotein receptor |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 11, Iss C, Pp 441-454 (2018) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| DOI: | 10.1016/j.omtn.2018.02.005 |
| Popis: | Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Current standard-of-care therapies only rarely lead to a functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss following treatment. The goal for next generation CHB therapies is to achieve a higher rate of functional cure with finite treatment duration. To address this urgent need, we are developing liver-targeted single-stranded oligonucleotide (SSO) therapeutics for CHB based on the locked nucleic acid (LNA) platform. These LNA-SSOs target hepatitis B virus (HBV) transcripts for RNase-H-mediated degradation. Here, we describe a HBV-specific LNA-SSO that effectively reduces intracellular viral mRNAs and viral antigens (HBsAg and HBeAg) over an extended time period in cultured human hepatoma cell lines that were infected with HBV with mean 50% effective concentration (EC50) values ranging from 1.19 to 1.66 μM. To achieve liver-specific targeting and minimize kidney exposure, this LNA-SSO was conjugated to a cluster of three N-acetylgalactosamine (GalNAc) moieties that direct specific binding to the asialoglycoprotein receptor (ASGPR) expressed specifically on the surface of hepatocytes. The GalNAc-conjugated LNA-SSO showed a strikingly higher level of potency when tested in the AAV-HBV mouse model as compared with its non-conjugated counterpart. Remarkably, higher doses of GalNAc-conjugated LNA-SSO resulted in a rapid and long-lasting reduction of HBsAg to below the detection limit for quantification, i.e., by 3 log10 (p < 0.0003). This antiviral effect depended on a close match between the sequences of the LNA-SSO and its HBV target, indicating that the antiviral effect is not due to non-specific oligonucleotide-driven immune activation. These data support the development of LNA-SSO therapeutics for the treatment of CHB infection. |
| Databáze: | OpenAIRE |
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