TY - JOUR
T1 - REVERSION OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS BY SKELETAL MUSCLE-DIRECTED FGF21 GENE THERAPY
AU - Bosch Tubert, Maria Fatima
AU - Jimenez, Veronica
AU - Sacristan Fraile, Victor
AU - Jambrina Pallares, Claudia
AU - Jaen Sitges, Maria Luisa
AU - Casaña Lorente, Estefania
AU - Muñoz Forero, Sergio Antonio
AU - Marcó, Sara
AU - Molas, Maria
AU - García Martínez, Miguel
AU - Grass, Ignasi
AU - León, Xavier
AU - Elias Puigdomenech, Ivet
AU - Ribera, Albert
AU - Elias, Gemma
AU - Sanchez Clares, Victor
AU - Vilà, Laia
AU - Casellas, Alba
AU - Ferré, Tura
AU - Rodó, Jordi
AU - Carretero Romay, Ana Maria
AU - Pumarola i Batlle, Martí
AU - Navarro Beltran, Marc
AU - Andaluz Martinez, Ana Maria
AU - Moll, Xavier
AU - Añor Torres, Sonia
AU - Franckhauser Vogel, Sylvie Laure
AU - Vergara, Mercedes
AU - Assumpta Caixàs Pedragós,
AU - Bosch, Fatima
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2024/12/4
Y1 - 2024/12/4
N2 - 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.
AB - 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.
KW - adeno-associated viral vectors
KW - fibroblast growth factor 21
KW - gene therapy
KW - insulin resistance
KW - metabolic dysfunction-associated steatohepatitis
KW - metabolic dysfunction-associated steatotic liver disease
KW - obesity
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85208770191&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2024.10.023
DO - 10.1016/j.ymthe.2024.10.023
M3 - Article
C2 - 39489916
SN - 1525-0016
VL - 32
SP - 4285
EP - 4302
JO - Molecular Therapy
JF - Molecular Therapy
IS - 12
ER -