Preclinical data for AAV-FGF21 gene therapy shows durable reversal of liver fibrosis

Liver-derived tissue with hepatic fibrosis (left) and after treatment (right) (© UAB – image adapted from V Jimenez, et. al Molecular Therapy (2024) DOI: 10.1016/j.ymthe.2024.10.023″)

Researchers from the Universitat Autonoma de Barcelona (UAB) in collaboration with clinicians from the Parc Taulí University Hospital in Sabadell have described in mice the long-term efficacy and safety of the intramuscular administration of a gene therapy for the treatment of MASH (metabolic dysfunction-associated steatohepatitis). The therapy is based on the genetic engineering of the skeletal muscle with the gene that encodes for the fibroblast growth factor 21 (FGF21)  using adeno-associated viral vectors (AAV-FGF21). The work is published in Molecular Therapy (1).

Reversal of liver fibrosis in mice

FGF21 is a key metabolic regulator that, upon the administration of the vectors in skeletal muscle, is sustainedly increased in bloodstream. One-time intramuscular administration of AAV1-FGF21 in obese male and female mice resulted in sustained increased circulating levels of FGF21 (more than a year in this study). The long-term treatment resulted in complete reversal of hepatic fibrosis while halting the development of liver tumors in animals followed for over 9 months following gene therapy treatment. AAV-FGF21 treatment also counteracted obesity, adiposity and insulin resistance in animals, which are significant drivers of MASH. The same treatment in dogs resulted in durable protein expression and biological activity in key metabolic tissues.

Most of MASH patients would be eligible

To facilitate clinical translation, the researchers have evaluated this therapy in dogs to assess the safety and therapeutic benefit in large animals. They have also characterized FGF21 circulating levels in a cohort of 500 obese, type 2 diabetes, and MASH patients, and conclude that most of them would be eligible for this gene therapy in the future. The results will be the basis for a future clinical trial. The UAB licensed this gene therapy program with AAV-FGF21 to the company Tramontane Therapeutics, now part of the US biopharmaceutical company Kriya Therapeutics, which will bring this approach now named  KRIYA-497 to the clinic in human MASH patients. “These results provide strong support for the durability and efficacy in animals of a one-time intramuscular AAV-FGF21-based gene therapy,” said Fátima Bosch, Ph.D., Professor in Biochemistry and Molecular Biology at UAB, Kriya Scientific Advisory Board Member, and director of the study.