Veronica Jimenez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaen, Estefania Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel Garcia, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sanchez, Laia Vilà, Alba Casellas, Tura Ferre, Jordi Rodó, Ana Carretero, Marti Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sonia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fatima Bosch
{"title":"Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy.","authors":"Veronica Jimenez, Victor Sacristan, Claudia Jambrina, Maria Luisa Jaen, Estefania Casana, Sergio Muñoz, Sara Marcó, Maria Molas, Miquel Garcia, Ignasi Grass, Xavier León, Ivet Elias, Albert Ribera, Gemma Elias, Victor Sanchez, Laia Vilà, Alba Casellas, Tura Ferre, Jordi Rodó, Ana Carretero, Marti Pumarola, Marc Navarro, Anna Andaluz, Xavier Moll, Sonia Añor, Sylvie Franckhauser, Mercedes Vergara, Assumpta Caixàs, Fatima Bosch","doi":"10.1016/j.ymthe.2024.10.023","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4285-4302"},"PeriodicalIF":12.1000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638876/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.10.023","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.