When Dr. Lawrence C.B. Chan and Dr. Vijay Yechoor of Baylor College of Medicine used a special gene therapy to induce the livers of mice with diabetes to make islet or beta cells, they knew they were on the road to developing an important new treatment for type 1 diabetes.
Getting control of glucose levels
However, when they tried their treatment in mice with an autoimmune form of type 1 diabetes, they could not restore the mice’s ability to control glucose levels in their blood. They hypothesized that part of the immune system – a form of T-cells – was attacking and destroying the new islet cells.
In a report at ENDO 2011, an annual international meeting of endocrinology researchers and physicians, the BCM team unveiled a newly tweaked part of their experiment that introduced a molecule called CD274 (or PDL1 [programmed death ligand]) , which inhibits activation of these T-cells, thus preventing them from attacking the new islet cells.
"We were able to induce production of new beta (or islet) cells in the liver, as we have in the past," said Chan, director of the federally-funded BCM Diabetes and Endocrinology Research Center. "This time, though, the cells survive. You can see the immune cells surrounding the islets, but they don’t kill them. The animals are no longer diabetic."
The team used a disarmed adenovirus as a vector to deliver a gene for a protein called neurogenin 3, which tells liver stem cells to become islet cells, and a gene for betacellulin, which causes these islet cells to grow. To this, they added the new molecule driven by a promoter that works only in the new islet cells.
"This is an attempt, using gene therapy, to make new islet cells and to protect them in mice with type 1 diabetes," said Yechoor, assistant professor of medicine – endocrinology and a senior author of the report. The mice with the autoimmune form of diabetes more closely mimic the disease in humans. Type 1 diabetes occurs when T-cells attack the individual’s own tissue, destroying the islet cells that make insulin.
About 5-10 percent of the 25.8 million people in the United States with diabetes have type 1diabetes.
Three genes are key
In the BCM study, the researchers gave 22 mice with autoimmune diabetes the three genes – neurogenin, betacellin and CD274 – delivered by the disarmed virus vector. Seventeen of these mice were able to control the glucose in their blood within two to four weeks, indicating that their bodies were making insulin. They also regained lost weight. Untreated mice with autoimmune diabetes continued to have high levels of glucose or sugar in their blood and to lose weight – all symptoms of uncontrolled diabetes.
As in earlier experiments with the gene therapy in mice with chemical diabetes, in these type 1 autoimmune diabetic mice, the treatment led to the appearance of clusters of cells that made large quantities of insulin in close proximity to the portal veins that carry blood from the intestine and abdominal organs to the liver.
These cells look like normal islet cells usually found in the pancreas. The CD274 molecules that attach to their surfaces prevent local activation of T-cells, allowing the new islet cells to do their job.
"This is targeted protection for the new islet cells," said Chan. That means the animals did not need drugs that suppress the immune system more generally.
Others who took part in this research include Dr. Rongying Li, Dr. Jeongkyung Lee, Dr. Mi-Sun Kim, Victoria Liu, Eric Buras and Dr. Kerem Ozer.
Funding for this research came from the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation.