Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 10 2021
21 10 2021
Historique:
received:
02
04
2021
accepted:
14
09
2021
entrez:
22
10
2021
pubmed:
23
10
2021
medline:
29
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34675338
doi: 10.1038/s41598-021-99008-2
pii: 10.1038/s41598-021-99008-2
pmc: PMC8531016
doi:
Substances chimiques
GABA-B Receptor Agonists
0
Phosphinic Acids
0
Propylamines
0
lesogaberan
4D6Q6HGC7Z
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20827Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK128289
Pays : United States
Organisme : NCATS NIH HHS
ID : UH3 TR002077
Pays : United States
Organisme : NCATS NIH HHS
ID : 4UH3TR002077
Pays : United States
Informations de copyright
© 2021. The Author(s).
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