2025
Mol Ther. 2025 Oct 11:S1525-0016(25)00842-1. doi: 10.1016/j.ymthe.2025.10.021. Online ahead of print.
Pancreatic transdifferentiation of NOD mouse livers prevented development of hyperglycemia
School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia. Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia. Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia; Discipline of Child and Adolescent Health, University of Sydney, Westmead, NSW 2145, Australia. School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia. Electronic address: ann.simpson@uts.edu.au.
Service type: Stock strains
Abstract
Type 1 diabetes (T1D) is caused by the autoimmune destruction of the pancreatic insulin-producing β cells. This study investigated a novel gene therapy approach to prevent disease development by replacing pancreatic β cell function with that from transdifferentiated liver cells. A clinically applicable third-generation lentiviral vector was used to deliver a cocktail of β cell transcription factors (Pdx1, NeuroD1, and MafA) to the portal vein of 5- to 6-week-old non-obese diabetic (NOD) mice. At the experimental endpoint (30 weeks), 100% of the NOD mice that received the lentiviral vector expressing the three β cell transcription factors were normoglycemic. Additionally, intraperitoneal glucose tolerance tests revealed that treated NOD mice could normalize blood glucose concentrations as efficiently as non-diabetic control animals. RT-PCR detected a range of pancreatic markers, such as somatostatin (Sst), Glut2, and most important, mouse insulin (INS1 and INS2), which was also found to be stored in the liver. Liver function tests remained normal. Collectively, these data show that expression of these β cell transcription factors led to partial pancreatic transdifferentiation and halted the development of hyperglycemia and abnormal glucose tolerance, which are the hallmarks of T1D. Thus, this approach holds substantial promise as a potential prophylactic strategy.
Keywords: gene therapy; lentiviral vector; liver; pancreatic transdifferentiation; type 1 diabetes; β cell transcription factors.
