1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)4285-4302
Number of pages18
JournalMolecular Therapy
Volume32
Issue number12
DOIs
Publication statusPublished - 4 Dec 2024

Keywords

  • adeno-associated viral vectors
  • fibroblast growth factor 21
  • gene therapy
  • insulin resistance
  • metabolic dysfunction-associated steatohepatitis
  • metabolic dysfunction-associated steatotic liver disease
  • obesity
  • type 2 diabetes

Fingerprint

Dive into the research topics of 'REVERSION OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS BY SKELETAL MUSCLE-DIRECTED FGF21 GENE THERAPY'. Together they form a unique fingerprint.

Cite this