If the human body were a stage, then proteins would rank among the lead actors in the play we call “Life.” These large biological molecules hold many starring roles, and their lines are dictated by information encoded in our genes. They are production powerhouses, regulating the basic processes of living and controlling countless functions. Many are enzymes that produce or use energy. Others regulate genes. Researchers are increasingly studying proteins as potential therapies for a variety of dread diseases because they can influence cell behavior by fueling or dampening certain molecular signals. Now University of Florida researchers have coaxed liver and pancreatic cells within diabetic mice into churning out insulin by injecting the animals with a naturally occurring protein called Pdx1, opening a new research avenue that someday could lead to safer treatments for type 1 diabetes. Pdx1 activates the genes controlling the development of the pancreas cells that make and release insulin to maintain safe levels of glucose in the body. The UF research team’s novel approach is described online in the journal Diabetes.
“Pdx1 is so special because it possesses a unique amino acid sequence that acts as a sort of molecular passport, allowing it to pass freely into cells, enter the nucleus and activate insulin production and release,” said lead scientist Dr. Li-Jun Yang, an associate professor of pathology, immunology and laboratory medicine at UF’s College of Medicine. Earlier research has shown that inserting the Pdx1 gene into liver or pancreas cells can induce insulin production, but most gene therapy methods use viruses to introduce a piece of genetically engineered DNA into cells. The disadvantage of such approaches is that researchers can never be certain the viruses are entirely harmless, Yang said. The idea with protein therapy is that eventually a person’s own cells could be reprogrammed to naturally produce the hormone, restoring the body’s ability to properly regulate blood sugar levels without having to use a potentially hazardous virus to slip corrective genes into the body or having to transplant pancreatic cells from someone else. That could eliminate the adverse effects sometimes associated with gene therapy and eliminate the need for lifelong suppression of the immune system so transplanted cells are not rejected, Yang said.
“We sought to see what happens if we inject highly pure Pdx1 protein into (the abdomens of) diabetic animals,” said Yang, who is also a founder and head of the scientific advisory board for Transgeneron Therapeutics Inc., which seeks to develop Pdx1 as a treatment for diabetes. UF holds a provisional patent on Pdx1 protein therapy.
“Amazingly, the treated mice did all the rest. Upon daily injection of this protein for 10 days into diabetic animals, their blood glucose levels became normalized within two weeks following the first injection,” Yang said. “We repeated the experiment six times, and we got the reproducible result every time. What is remarkable is that the protein also promotes regeneration of insulin-producing cells in the pancreas, allowing the diabetic mice to become normal.”
Yang said there is now reason to believe normal blood sugar levels can be maintained for long periods, suggesting that an infrequent Pdx1 injection might someday replace daily insulin injections. Even more importantly, the reprogrammed and regenerated cells should make and release insulin, automatically maintaining safe blood sugar levels, she said.
Still, the approach will have to be tested in studies that assess its safety before scientists could conduct patient trials to determine whether it works in humans.