Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

• DOI: 10.1016/j.stem.2017.11.020
• Publication Date: 2018-01-04T16:47:24Z
• Authors: Xiangwei Xiao; Ping Guo; Chiyo Shiota; Ting Zhang; Gina M. Coudriet; Shane Fischbach; Krishna Prasadan; Joseph Fusco; Sabarinathan Rama...; Piotr Witkowski; Jon D. Piganelli; George K. Gittes
• Keywords: Blood Glucose; Homeodomain Proteins; Gene Expression Profiling; Genetic Therapy; Mice, SCID; Dependovirus; Cellular Reprogramming; Glucagon; Diabetes Mellitus, Experimental; 3. Good health; Mice, Inbred C57BL; Diabetes Mellitus, Type 1; Glucagon-Secreting Cells; Hyperglycemia; Insulin-Secreting Cells; Alloxan; Animals; Humans; Insulin; Lectins, C-Type; Receptors, Immunologic

Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin+ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.