Pancreatic transdifferentiation of NOD mouse livers prevented development of hyperglycemia

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.