Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B
| العنوان: | Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B |
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| المؤلفون: | Ricardo Ramirez, Li Li, William E. Delaney, Stephan Menne, Sarina Ma, Changsuek Yon, Don Kang, Jason Chamberlain, Christian Voitenleitner, William Rowe, Ruth Chu, Dhivya Ramakrishnan, Magdeleine Hung, Manasa Suresh, Divya Pattabiraman, Stephane Daffis, Paul J. Cote, Rex Santos, Bei Li, Simon P. Fletcher, Scott Balsitis, Sandra Spurlock, Mish Michael R, Jim Zheng, Richard L. Mackman |
| المصدر: | Hepatology (Baltimore, Md.) |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Agonist, medicine.drug_class, Viral Hepatitis, viruses, Pharmacology, Virus Replication, medicine.disease_cause, Antiviral Agents, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Immune system, Antigen, medicine, Animals, Hepatitis B Virus, Woodchuck, Humans, Hepatitis Antibodies, Hepatitis B virus, Hepatology, biology, business.industry, Woodchuck hepatitis virus, Hepatitis Antigens, Original Articles, biochemical phenomena, metabolism, and nutrition, Hepatitis B, biology.organism_classification, medicine.disease, digestive system diseases, Disease Models, Animal, Pyrimidines, 030104 developmental biology, Toll-Like Receptor 8, Marmota, DNA, Viral, biology.protein, Original Article, 030211 gastroenterology & hepatology, Antibody, Hexanols, business, Viral load |
| الوصف: | Background and aims GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 in clinical development for the treatment of chronic hepatitis B. In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus. Approach and results WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688, or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusions Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks; the identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. |
| تدمد: | 1527-3350 0270-9139 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4412f0d4ba1f1e34adb633cd495c9bc8 https://doi.org/10.1002/hep.31255 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4412f0d4ba1f1e34adb633cd495c9bc8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15273350 02709139 |
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