Work

Repositioning of a Novel GABA-B Receptor Agonist, AZD3355 (Lesogaberan), for the Treatment of Non-alcoholic Steatohepatitis

Year: 2021

Type: preprint

Abstract: 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, aSMA and TNF-a mRNA as well as secreted collagen1a1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development in a robust murine model of NASH, which was comparable to activity of obeticholic acid, an advanced investigational therapy for this disease. These data identify a well-tolerated clinical stage asset as a novel 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.

Source: Research Square

DOI: 10.21203/rs.3.rs-386482/v1