Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD)

Metabolic dysfunction-associated steatohepatitis (MASH), represents a threat to global health. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of a non-mitogenic (NM)-FGF19 mRNA-formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH). NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for six weeks. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BA) levels and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the downregulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19 demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19 may be mechanistically relevant. Overall, our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations. Overall design: 24-week-old C57BL/6NTac male mice were feeded with normal chow diet or high-fat diet (HFD) in parallel for 21 weeks. HFD mice where separated into baseline, control and NM-FGF19 groups. Baseline mice were sacrificed the week before treatment to verify that HFD mice had reached the MASH stage. All mice were then treated weekly for six weeks with mRNAs-LNPs while mantaining diet. In lean mice (normal chow) and control HFD mice a Control-mRNA was used, while NM-FGF19 group was treated with NM-FGF19 containing mRNA-LNPs. 24 hours after last mRNA-LNPs administration mice were sacrificed and liver tissues prepared for RNA extraction and sequencing.