Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy
Verónica Jiménez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaén, Estefanía Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel García, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sánchez, Laia Vilà, Alba Casellas, Tura Ferré, Jordi Rodó, Ana María Carretero, Martı́ Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sònia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fátima Bosch
Abstract
The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.