Gene Therapy Reverses Autoimmune Diabetes in Mice

Reversing autoimmune type 1 diabetes without immunosuppression has proven to be extremely difficult, but in a study published today in Cell Stem Cell, researchers at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine report achieving that outcome in mice using gene therapy.

In type 1 diabetes, the body mistakenly recognizes the insulin-producing ‘beta’ cells in the body as foreign and kills them, resulting in high blood sugar levels. Patients require lifelong insulin therapy either through injections or an insulin pump. The current study however, represents a major advance in efforts to develop a long-term therapeutic approach by stimulating the body’s own pancreatic cells to produce insulin.

“We have shown for the first time that gene therapy can be specifically and effectively targeted to reverse autoimmune diabetes in mice without the use of any immunosuppressant drugs,” said George K. Gittes, M.D., chief of pediatric surgery at Pitt’s School of Medicine and the Benjamin R. Fisher Chair in Pediatric Surgery, at Children’s Hospital.

Gittes and his team reprogrammed non-insulin producing pancreatic ‘alpha’ cells into insulin producing beta cells by introducing two genes with the help of a virus commonly used in gene therapy. By using a recently developed method called ‘pancreatic intraductal viral infusion,’ the researchers directly delivered the therapeutic virus to the pancreas, thus using a much smaller amount of virus when compared to traditional gene therapy injections and reducing the chances for side effects.

When tested in a mouse model in which diabetes had been induced by killing off beta cells with a toxin, Gittes and his team found that the gene therapy reversed the diabetes by reprogramming alpha cells into beta cells, which produced insulin and returned blood sugar levels to normal.

The team then evaluated the approach in a mouse model of autoimmune type 1 diabetes. While these mice normally die within approximately five weeks of the onset of high blood sugar due to the persistence of excessive blood sugar, the gene therapy resulted in conversion of alpha cells into beta cells and prolonged blood sugar control for about 16 weeks in the mice tested.

Importantly, the newly reprogrammed cells were not destroyed due to an autoimmune reaction for approximately four months, a significantly longer time when compared to other methods such as beta cell transplantation in which the cells are killed immediately. The reason behind the protection from autoimmune attack is still unclear, but is likely linked to the location of the newly reprogrammed beta cells in the pancreas, according to the authors.

“This method to deliver a gene therapy directly to the pancreas could easily be applied to humans, as similar pancreatic injections are routinely performed as part of a non-surgical endoscopic procedure,” said Gittes.

The researchers currently are testing the therapy in a non-human primate model, and if proven effective, could soon initiate clinical trials.

Additional authors on the study are Xiangwei Xiao, M.D., Ph.D., Ping Guo, Ph.D., Chiyo Shiota, Ph.D., Ting Zhang, Ph.D., Gina Coudriet, Ph.D., Shane Fischbach, medical student, Krishna Prasadan, Ph.D., Joseph Fusco, M.D., and Jon Piganelli, Ph.D., all from the Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh; and Sabarinathan Ramachandran, Ph.D., and Piotr Witkowski, Ph.D., of the University of Chicago.

Funding was provided by National Institutes of Health grants R01DK098196, R01DK111460 and R01DK112836; Juvenile Diabetes Research Foundation grant 1-INO-2014-167-A-V; Children's Hospital of Pittsburgh of UPMC, University of Chicago DRTC Grant P30DK020595; National Center for Advancing Transitional Sciences grant UL1TR000430.