| International Session（Workshop）1(JSGE・JSH・JSGCS) |
| Thu. November 2nd 14:30 - 17:00 Room 11: Portopia Hotel South Wing Topaz |
| Combination therapies with synergistic therapeutic effects to achieve functional cure by RNA destabilizer | |||
| Takehisa Watanabe1, Sanae Hayashi1, Yasuhito Tanaka1 | |||
| 1Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University | |||
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| Background and Aim: We have developed and are conducting preclinical studies of SAG compounds (SAG-comp), which is novel oral drug with excellent HBsAg-lowering activity and tolerability, to achieve a functional cure. However, the best combination of SAG-comp with other drugs is still under investigation. The aim of this study was to investigate the possibility of combining SAG-comp with nucleos(t)ide analogue (NUC) or capsid assembly modulator (CAM), replication inhibitors. Methods: The therapeutic efficacy of combination therapy with SAG-comp and entecavir (ETV) was evaluated in a human liver chimeric mouse model (PXB mouse). cccDNA in hepatocytes was quantified by digital PCR. The combined effect of SAG-comp and GLS4, a CAM, was analysed by Northern blotting using HepAD38 cells. Results: The efficacy of SAG-comp in combination therapy with ETV significantly reduced both serum HBsAg and HBV-DNA, and as well as cccDNA in hepatocytes. GLS4 monotherapy did not reduce intracellular HBV-RNA. In contrast, SAG-comp monotherapy significantly reduced HBV-RNA, but pgRNA was detectable. GLS4+SAG-comp combination therapy further reduced HBV-RNA, and then pgRNA bands were undetectable. These data were supported by in vivo PXB mice. Conclusions: SAG-comp potently suppressed HBsAg and reduced cccDNA in combination with NUC. In addition, SAG-comp showed an enhanced effect on HBV-pgRNA when combined with CAM, suggesting that SAG-comp in combination with NUC and/or CAM would have synergistic effects for functional cure. |
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Index Term 1: RNA destabilizer Index Term 2: HBV |
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