UAB researchers cure liver disease MASH by a one-time gene therapy

Researchers from the Universitat Autònoma 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, a liver disease that affects approximately 40 million people in the United States and Europe.

The therapy developed by the UAB researchers is based on the genetic engineering of the skeletal muscle with the gene that encodes for the fibroblast growth factor 21 protein using adeno-associated viral vectors (AAV-FGF21 vectors). FGF21 is a key metabolic regulator that, upon the administration of the vectors in skeletal muscle, is sustainedly increased in bloodstream (more than a year in this study). This treatment mediates long-term reversal of liver fibrosis and MASH, counteracts obesity, excessive fat accumulation, insulin resistance characteristic of type 2 diabetes, and the development of liver tumors both in female and male mice.

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 Inc., now part of the biopharmaceutical company Kriya, which will bring this approach to the clinic in human MASH patients. "Our gene therapy based on AAV-FGF21 can be transformative for patients with MASH, a disease that requires safe, effective and long-lasting treatments," explains UAB researcher Fatima Bosch, who led the research.

Obesity and type 2 diabetes, precursors of MASH

The global epidemics of obesity and type 2 diabetes are risk factors for the development of liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), or "fatty liver disease," is the most common chronic liver disease worldwide, an epidemic whose prevalence can reach 27% of the adult population in some countries. It begins with an excessive accumulation of lipids in the liver that can worsen into severe metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation, lesions in the liver cells (hepatocytes) and fibrosis. In advanced stages, MASH is associated with severe liver diseases, such as cirrhosis, liver cancer and end-stage liver disease, with high mortality. For Dr. Fatima Bosch, “the gene therapy strategy we have developed could be a major advance in the treatment not only of patients with MASH, but also of other metabolic diseases and related comorbidities that affect millions of people worldwide.”

The research, led by Professor Fatima Bosch, director of the UAB Center of Animal Biotechnology and Gene Therapy (CBATEG), professor of the Department of Biochemistry and Molecular Biology at the UAB and member of the CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM; ISCIII), was conducted by researchers from CBATEG and from the Department itself, especially Veronica Jimenez and Victor Sacristan (first authors of the manuscript), together with researchers from the Department of Animal Health and Anatomy and the Department of Animal Medicine and Surgery of the School of Veterinary Medicine of the UAB; the Parc Taulí Research and Innovation Institute (I3PT-BUSCA); the Teaching Unit of the School of Medicine of the UAB at the Parc Taulí University Hospital in Sabadell; the Departments of Pathology and Endocrinology and Nutrition of the Parc Taulí Hospital, and from the CIBER of Liver and Digestive Diseases (CIBEREHD). The work is published today in Molecular Therapy, the founding journal of the American Society of Gene & Cell Therapy (ASGCT).

Reference article:
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 and Fatima Bosch. Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. Molecular Therapy (2024) DOI: 10.1016/j.ymthe.2024.10.023