The discovery of insulin by Canadian Nobel laureate Sir Frederick G. Banting, M.D., and his student Charles H. Best, M.D., in the early 1920s transformed childhood diabetes from a death sentence to a serious chronic disease, but the therapy they pioneered—multiple daily insulin injections—is no cure. That goal has remained elusive for nearly a century, but School of Medicine researchers are finding new success by treating the underlying autoimmune reactions that cause diabetes in children and young adults. By protecting and preserving a patients’ own insulin production, the new approaches present the exciting prospect of preventing the disease altogether.
Though the symptoms of type 1 diabetes, sometimes called juvenile-onset diabetes, emerge abruptly, researchers now know that the condition develops over a long period. Overactive immune T cells mistakenly attack and destroy the insulin-producing beta cells in the pancreas in a battle that can last for years. That realization opened a window of opportunity for therapy, which Kevan Herold, M.D., professor of immunobiology and medicine, and his colleagues are aiming to exploit.
“We know that when people first present with diabetes, they still make substantial amounts of insulin,” Herold explains. “Over a period of years, they gradually lose that ability. Our idea is to stop the ongoing process of immunologic destruction of insulin-producing cells.”
To do that, Herold and his collaborator Jeffrey A. Bluestone, Ph.D., of the University of California at San Francisco, have developed an antibody that quiets the attacking T cells. In a series of small clinical studies that began in 1999 and 2002, Herold and colleagues demonstrated that patients who received a two-week treatment with the antibody when their diabetes first appeared still had substantial insulin production up to two years later, while untreated control subjects showed the expected continued decline in insulin levels. That antibody is now undergoing testing in larger clinical trials, sponsored by a Maryland biotech company in collaboration with the Juvenile Diabetes Research Foundation International (JDRF), with a target completion date of 2011.
In the meantime, Herold is running his own follow-up experiments with the antibody. His current studies aim to test if booster treatments of the antibody can prolong its effect on insulin production. Also, he wants to know if treatment can still work for people who have had diabetes for a while but continue to make some of their own insulin.
The antibody is not a cure. After treatment, patients still need daily insulin injections, but they need significantly less. Preserving some natural pancreas function helps them to regulate their blood sugar, which is likely to stave off both dangerous swings in blood sugar in the short term, and long-term complications that can include heart disease, high blood pressure, blindness and kidney disease. At the same time, an important plus of the immune treatment is that it does not result in long-term immunosuppression, which carries a risk of infection or cancer. Instead, the antibody appears to produce a state of immune tolerance, where the T cells are retrained and cease to attack vulnerable beta cells. One important question Herold wants to answer is how long that effect can be maintained.
It seems certain that any future cure will feature some form of immune control. Promising approaches include stem cell replacement therapy and beta-cell transplants, but in either case, the new tissues created by these techniques will need protection from the same immune onslaught that destroyed their predecessors. Along those lines, researchers elsewhere are now testing the antibody developed by Herold and Bluestone in conjunction with beta-cell transplants.
But the most exciting prospect for Herold is finding out whether the antibody can actually prevent diabetes in people who are not yet sick, but appear to be headed that way. With support from The National Institutes of Health (NIH), Herold now directs the Trial Net Center at Yale, which promotes studies of the treatment and prevention of type 1 diabetes. A diabetes prevention trial—in which subjects will include relatives of people with type 1 diabetes who still have robust insulin production, but show signs of an ongoing immune reaction to their beta cells and subtle changes in blood sugar regulation—is expected to be launched by the Yale center by year’s end. Such people do not meet the diagnostic criteria for diabetes, says Herold, but as teenagers, they have a 90 percent chance of developing diabetes within six years. The trial will test whether antibody treatment can protect the beta cells from destruction, keep insulin levels normal and permanently prevent the onset of diabetes, making daily insulin injections unnecessary.
Since coming to Yale two years ago as the first new faculty to join the Human Translational Immunology program directed by Jordan S. Pober, M.D., Ph.D., professor of immunobiology, dermatology and pathology, Herold has joined forces with Richard A. Flavell, Ph.D., chair and Sterling Professor of Immunobiology, to develop new mouse models of diabetes.
Flavell pioneered the use of genetically engineered mice to study the fundamental principles of immune systems. Now, using a combination of genetic modifications and human stem cells, he is leading an effort to engineer a new mouse that shares the most important features of the human immune system. (see “Petri dishes, power chords”)
The project was launched by a $17 million grant to Flavell and colleagues from the Bill and Melinda Gates Foundation to develop the mice for the rapid development and testing of new HIV/AIDS vaccines, but the human immune-system mouse is also eminently qualified for studying diabetes. “There have been a lot of resources that the Gates Foundation has put into this project, and we want to take advantage of that,” Herold says. “By making a few tweaks, we can develop new models that can be used to study autoimmune diseases including type 1 diabetes. So we’re not reinventing the wheel; we’re taking advantage of advances that are moving forward in parallel fields and applying them to diabetes.”
Once developed, the mice will be invaluable for discovering and testing new drug candidates, and for understanding how treatments work. In support of the effort, the JDRF recently granted Flavell and Herold $7.5 million to establish the JDRF Center for Developing Immunotherapies for Diabetes at Yale, with the express goal of generating models of diabetes in the new human immune-system mice. In return for that investment, Herold says, the new mice should “make it a lot easier, a lot faster and a lot cheaper to develop new therapies.”