Researchers have developed a gene therapy that restores normal blood glucose levels in diabetes by reprogramming alpha cells in the pancreas into insulin-producing beta cells.
Dr. George Gittes, a professor of surgery and of pediatrics at the University of Pittsburgh School of Medicine in Pennsylvania, and team led the study. Their findings were published in the journal Cell Stem Cell.
The immune system that usually destroys germs and foreign substances mistakenly launches an attack on the insulin-producing beta cells that are found in the pancreas, which then results in high blood glucose levels.
Over time, type 1 diabetes can have a significant effect on major organs and cause heart and blood vessel disease, damage to the nerves, kidneys, eyes, and feet, skin and mouth conditions, and complications during pregnancy.
Researchers in the type 1 diabetes field have aimed to develop a treatment that preserves and restores function to beta cells, which would, in turn, replenish insulin, responsible for moving blood glucose into cells for energy.
One barrier to this solution is that the new cells that arise from beta cell replacement therapy would likely also be destroyed by the immune system.
To overcome this hurdle, the team hypothesized that other, similar, cells could be reprogrammed to behave in a similar way to beta cells and produce insulin, but which are different enough not to be recognized and destroyed by the immune system.
Alpha cells reprogrammed into beta cells
The team engineered an adeno-associated viral (AAV) vector that delivered two proteins — Pdx1 and MafA — to the mouse pancreas. Pdx1 and MafA support beta cell proliferation, function, and maturation, and they can ultimately transform alpha cells into insulin-producing beta cells.
Alpha cells were the ideal candidates for reprogramming. They are abundant, similar to beta cells, and located in the pancreas, which would all help with the reprogramming process.
Analysis of the transformed alpha cells showed a nearly complete cellular reprogramming to beta cells.
Dr. Gittes and team demonstrated that in a mouse model of diabetes, blood glucose levels were restored for about 4 months with gene therapy. The researchers also found that Pdx1 and MafA transform human alpha cells into beta cells in vitro.
"The viral gene therapy appears to create these new insulin-producing cells that are relatively resistant to an autoimmune attack," explains Dr. Gittes. "This resistance appears to be due to the fact that these new cells are slightly different from normal insulin cells, but not so different that they do not function well."
The future of diabetes gene therapy
AAV vectors are currently being researched in human gene therapy trials and could be delivered to the pancreas through a non-surgical endoscopic procedure, eventually. However, the researchers caution that the protection observed in the mice was not permanent, and 4 months of restored glucose levels in a mouse model "might translate to several years in humans."
"This study is essentially the first description of a clinically translatable, simple single intervention in autoimmune diabetes that leads to normal blood sugars," says Dr. Gittes, "and importantly with no immunosuppression."
"A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy."
Dr. George Gittes
The scientists are testing the gene therapy in non-human primates. If successful, they will begin working with the Food and Drug Administration (FDA) to approve use in humans with diabetes.