Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis
| Autor: | Christine Becker, Leslie P. Cousens, Ryan Hicks, Scott L. Friedman, Joel T. Dudley, Jacqueline Buros Novik, Dipankar Bhattacharya, Maria Isabel Fiel, Björn Magnusson, Nicolas Goossens, Anna Backmark, Benjamin Readhead |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Agonist Lesogaberan MAPK/ERK pathway medicine.drug_class Science Metabolic disorders Pharmacology Article Cell Line Mice chemistry.chemical_compound Non-alcoholic Fatty Liver Disease In vivo Animals Humans Medicine Aged Multidisciplinary Propylamines Drug discovery business.industry Drug Repositioning Gastroenterology Obeticholic acid Middle Aged medicine.disease Phosphinic Acids digestive system diseases Mice Inbred C57BL Disease Models Animal Drug repositioning Liver chemistry GABA-B Receptor Agonists Hepatic stellate cell Female Steatohepatitis business |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-17 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-021-99008-2 |
| Popis: | Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials. |
| Databáze: | OpenAIRE |
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