Researchers at the University of Wisconsin School of Medicine and Public Health are one step closer to developing a gene therapy for Type 1 diabetes mellitus – a development that could one day eliminate the need for daily insulin shots and provide a way to better regulate glucose metabolism, a factor critical for preventing the most problematic complications of the disease.

The study, reported in the June 27, 2013, issue of the journal PLOS ONE, describes a small sequence of DNA that, when injected into the veins of diabetic rats, create insulin-producing cells that help normalize blood sugar levels and perfect the regulation of glucose metabolism. It is the first known study to demonstrate how a DNA-based insulin gene therapy has the potential to treat type 1 diabetes.

“Even we were surprised that a single injection could provide perfect glycemic control for up to six weeks,” says Hans Sollinger, the Folkert O. Belzer Professor of Surgery at the UW School of Medicine and Public Health. “After receiving the therapy, the diabetic rats had insulin and glucose levels that resembled exactly what you would find in healthy animals.” 

The DNA sequence of the therapy works by sensing an increase in glucose concentrations in the body (such as after a meal) and then, with the help of a glucose inducible response element (GIRE), prompts the injected DNA to produce insulin, similar to the way normal pancreatic cells do. But instead of targeting pancreatic cells, the therapy exclusively targets the liver. 

“We chose the liver as the ideal target for this therapy because of its ability to regenerate,” says Sollinger. “In order for the therapy to be effective, the DNA needs to enter and attach to millions of cells, so the liver’s ability to replace dead cells was an obvious advantage. The treatment essentially makes the liver function like a mini-pancreas.”

Type 1 diabetes mellitus results from the autoimmune destruction of insulin-producing cells of the pancreas. There is no cure for type 1 diabetes; insulin therapy, which must be given multiple times per day, is the sole effective treatment. Although injectable insulin preserves life, maintaining glucose control is difficult to do and often causes chronic hyperglycemia, which can lead to end-stage kidney failure, blindness, and amputations.

Based on serum lipid profiles and other markers of liver function, the study showed that a single treatment effectively protected the diabetic rats from many of the long-term diabetes-associated damage. Sollinger says the therapy has the potential to meet a set of goals he established when he first started this research more than 20 years ago.

“I was determined to develop a therapy that would not only make daily insulin injections obsolete but would also be suitable for all patients with type 1 diabetes, that would require no major operative procedures, and that would be affordable,” Sollinger says. “This study shows we’re on the right track.”

Early evidence of the potential success of the therapy inspired Sollinger and one of his colleagues, Tausif Alam, to start Insulete Inc., a private research firm dedicated to improving the treatment of type 1 diabetes. Insulete, which stands for “insulin obsolete,” developed and patented the minicircle DNA used to treat the diabetic rats. The Wisconsin Alumni Research Foundation (WARF) owns the patent on GIRE and leases it to Insulete Inc. for their ongoing research.

Currently, Sollinger and his colleagues are trying to increase the time interval between treatment injections from six week to six months. Insulete is currently seeking permission from the FDA to begin phase one trials in humans in spring 2014.

In the US, approximately 1 to 1.5 million patients, most of them children, have been diagnosed with type 1 diabetes. The economic cost in the United States is estimated at $8 billion to $14 billion per year. The study was funded, in part, by a grant from the Juvenile Diabetes Research Foundation and the Roche Organ Transplant Foundation.