A novel GLP-1and FGF21 fusion protein for the treatment of non-alcoholic steatohepatitis (NASH)

Abstract

Purpose: The objective of this study was to develop and produce a novel fusion protein combining GLP-1 and FGF21, aiming to achieve synergistic pharmacological effects by targeting dual pathways, and subsequently validate these effects in a NASH model. Method: We utilized C57Bl/6J mice to establish an HFD/CCl4 NASH model, with the primary aim of assessing the drug efficacy across low, medium, and high (0.3, 1, 3mpk) dose groups administered twice weekly for 28 days. The secondary objective was to investigate the impact of long-term storage (-20°C, 30M) on HSP763-01's efficacy and to evaluate the drug effectiveness of the high dose (3mpk) group given twice a week after the use of CCl4 for 2 weeks for 28 days. Results: The animal pharmacological experiment of HSP763-01 demonstrated a significant reduction in body weight without apparent appetite suppression. Analysis of blood biochemical indicators revealed a marked decrease in TG, TCHO, LDL, and blood sugar levels with a significant dose-dependent effect. Additionally, Liver tissue analysis indicated notable alleviation of liver fatty degeneration and ballooning degeneration, as well as partial relief of lobular inflammation with a significant dose-dependent effect. However, due to the severe liver fibrosis induced by CCl4 in mice (3rd grade), HSP763-01 exhibited limited efficacy in alleviating fibrosis. Conclusion: HSP763-01 exhibited a clear dual target of GLP-1 and FGF21, which has been demonstrated by a robust response to the HFD/CCl4 model, showing a marked improvement in lipid metabolism, lowering of blood glucose, weight loss, significant alleviation of liver steatosis, ballooning, and partial relief of lobular inflammation and fibrosis.