A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model.
Although growth factors have significant therapeutic potential because of their regenerative functions, their poor pharmacokinetics and low stability hinder their therapeutic application. Nonalcoholic steatohepatitis (NASH) is characterized by lipid accumulation, inflammation, and fibrosis in the liver, which can progress to life-threatening conditions such as cirrhosis and liver cancer. The hepatocyte growth factor (HGF)-Met receptor pathway has been proposed as a potential therapy for liver diseases including NASH due to its effects on liver regeneration, but the short half-life of recombinant HGF limits its clinical use. Here, we designed a Met agonist with a long half-life by grafting two Met-binding macrocyclic peptides into loops of the crystallizable region (Fc) of immunoglobulin. This surrogate Met agonist ameliorated liver fibrosis and inflammation in a mouse model of NASH, indicating its potential therapeutic use. This study provides a foundation to develop growth factor and cytokine mimetics and to expand their therapeutic applications. Overall design: RNA-seq analysis of murine hepatic tissue of 2 experimental sets: 1) C57BL/6J inbred male mice (n=20) fed a CDAHF diet for 12 weeks. Then, 2 weeks of HFD and either 4.3 mg/kg Fc  (control n = 10), or 5 mg/kg Fc(mML1)B3 (n = 10) once a week . 2) C57BL/6J inbreed mice (n=16) were fed a CDAHFD for 12 weeks, Then 10 days of  standard diet and either 4.3 mg/kg Fc (control n = 9), or 5 mg/kg of Fc(mML1)B3 (n = 7) at days 1, 4, and 7.