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2024-10-25

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cc-by-nc-nd (c) Miquel Garcia, et al., 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/217195

Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy

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https://doi.org/10.1016/j.ymthe.2024.10.023

Resum

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

Matèries

Múscul estriat, Teràpia genètica

Matèries (anglès)

Striated muscle, Gene therapy

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Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

Citació

GARCIA, Miquel, JIMÉNEZ PERALES, Verónica, SACRISTÁN, Víctor, JAMBRINA, Claudia, JAÉN, Maria luisa, CASANA, Estefania, MUÑOZ, Sergio, MARCÓ, Sara, MOLAS LAPLANA, Maria, GRASS, Ignasi, LEÓN, Xavier, ELIAS, Ivet, RIBERA SÁNCHEZ, Albert, ELIAS, Gemma, SÁNCHEZ, Víctor, VILÀ PRATS, Laia, CASELLAS, Alba, FERRÉ MASFERRER, Tura, RODÓ TOMÁS, Jordi, CARRETERO ROMAY, Ana, PUMAROLA I BATLLE, Martí, NAVARRO BELTRÁN, Marc, ANDALUZ MARTÍNEZ, Anna, MOLL, Xavier, AÑOR TORRES, Sònia, FRANCKHAUSER, Sylvie, VERGARA, Mercedes, CAIXÀS I PEDRAGÓS, Assumpta, BOSCH I TUBERT, Fàtima. Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. _Molecular Therapy_. 2024. Vol. 32, núm. 4285-4302. [consulta: 14 de gener de 2026]. ISSN: 1525-0016. [Disponible a: https://hdl.handle.net/2445/217195]

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