Abstract
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease, which is driven by the global obesity and type 2 diabetes epidemic. NASH is characterized by liver inflammation and fibrosis that can progress to cirrhosis, liver failure, cancer and death. Currently, NASH is an unmet medical need. Recent studies revealed the therapeutic potential of fibroblast growth factor 21 (FGF21) analogues/mimetics against NASH in pre-clinical models and in human patients, although periodic administrations are required and immunological responses may raise due to the use of engineered, non-native, proteins. Here, we demonstrated that adeno-associated viral (AAV) vector-mediated-FGF21 genetic engineering of skeletal muscle of high-fat diet-fed obese and insulin-resistant mice resulted in increased circulating levels of native FGF21. AAV-FGF21-treatment normalized liver fat content, liver inflammatory and fibrotic markers and counteracted hepatocyte damage, consistent with NASH resolution. It also precluded progression from NASH to cirrhosis and hepato-cellular carcinoma. Moreover, circulating FGF21 reversed adipose tissue hypertrophy and inflammation, increased energy expenditure, normalized glycemia and insulinemia, and increased insulin sensitivity. Scale-up of muscular FGF21 gene transfer to large animals also successfully resulted in long-term secretion of biologically active FGF21 and therapeutic effects in key target tissues, in the absence of adverse events. All these results point out the potential of the AAV-FGF21-mediated gene therapy to treat NASH and support the clinical translation of the approach. Disclosure V. Jimenez: None. V. Sacristán: None. C. Jambrina: None. M. Jaén: None. S.A. Munoz: None. E. Casana: None. M. Garcia: None. I. Grass: None. X. Leon: None. I. Elias: None. A. Ribera: None. G. Elias: None. V. Sanchez: None. A. Casellas: None. T. Ferré: None. M. Molas: None. F. Bosch: None.
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