Effect of GB1107, a novel galectin-3 inhibitor on pro-fibrotic signalling in the liver

Background and purpose: Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease.

Experimental approach: Liver fibrosis was induced by administration of CCl₄ twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl₄ treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the NextSeq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms.

Key results: GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1,659 DEGs were identified with CCl₄ treatment compared to control. Pathways enriched in up-regulated genes in the CCl₄ group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl₄ control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl₄ induced gene changes.

Conclusions and implications: GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis.