News: Researcher's diabetes quest earns reward for excellence

Prof Len Harrison, of the Walter and Eliza Hall Institute, has been awarded the David Rumbough award for scientific excellence by the Juvenile Diabetes Research Foundation International for his research towards finding a cure for type 1 diabetes.

The award is presented annually in recognition of outstanding achievements in diabetes research and service to JDRF. Harrison is only the second international recipient of the award.

Harrison and his team at WEHI's autoimmunity and transplantation division are developing a number of approaches to delay the onset of, or even cure, type 1 diabetes by preventing the immune system from attacking and destroying the insulin-producing beta cells of the pancreas.

One method, currently in clinical trials, uses a nasal insulin spray to induce an immune response in the mucous membranes of the nose and lungs that in diabetic NOD mice protects against development of the autoimmune disease.

The second method is based on the genetic modification of bone marrow derived stem cells to over-express proinsulin, which can then be transplanted back into the host to instruct the immune system to leave insulin-producing cells alone.

"Both methods are ways of inducing immune tolerance to protect against diabetes," Harrison says. "And both work in the NOD mouse model of diabetes to induce antigen specific protection."

According to Harrison, proinsulin -- the precursor form of insulin -- is the major driver of the autoimmune response that kills pancreatic beta cells in humans and in the NOD mouse model. So by inducing immune tolerance, a process that instructs the immune system to ignore proinsulin and insulin, the autoimmune response is averted and the disease is prevented.

So far, the results of the nasal insulin spray clinical studies have been encouraging. The treatment has been shown to be safe and 15 per cent of the children receiving the spray in a pilot trial have gone on to develop diabetes, compared to nearly 40 per cent of controls. "We can't say we have cured diabetes, but we can at least say that we haven't accelerated its progress," Harrison says.

Now Harrison and his collaborator Assoc Prof Peter Colman, head of the diabetes and endocrinology department at Royal Melbourne Hospital, are planning a larger multi-centre trial in Australia and New Zealand, which is being supported by the Diabetes Vaccine Development Centre, a joint venture between the JDRF and Australia's NHMRC.

The trial will involve the screening of up to 12,000 children and young adults at risk of developing diabetes, based on the presence of one or more close relatives with diabetes, to see if preliminary signs of the disease are present. The researchers will look for antibodies against insulin/proinsulin, glutamic acid decarboxylase and tyrosine phosphatase-like islet antigen 2, which are all correlated with increased risk of disease, as well as whether the beta cells are functioning normally, and the level of insulin resistance, also associated with increased risk.

About 200 children with a moderate risk of developing diabetes -- characterised by the presence of two out of three of the antibodies but normal beta cell function -- will be treated with nasal insulin for one year, and then followed up for another five years to see if diabetes develops.

"This is based on completed trials where we showed that nasal insulin induced immune changes consistent with mucosal tolerance to insulin and which in the mouse model was associated with protection from disease development," Harrison said. "We don't know how long the tolerance will last but we hope to find out in the course of the trial."

Eventually the researchers hope to expand the treatment to use proinsulin and the other antigens associated with development of diabetes, Harrison said.

A stem cell-based prophylactic treatment for diabetes, however, is years away from clinical use. According to Harrison, while the technique has been demonstrated to prevent the onset of diabetes in NOD mice, there are several hurdles to overcome before human application. Firstly, a method for safely getting the genes into the stem cells is required -- the researchers are currently looking at various non-retroviral delivery systems.

A more pressing problem is that in mouse experiments, the immune system is conditioned by irradiation to knock out the immune system prior to transplanting the genetically modified stem cells back into the host. This prevents immunological rejection from occurring, but is not an appropriate step to take in humans.

"We need to work out how to condition the immune system without impairing it," Harrison says. It's a challenge he believes will be overcome as more knowledge of how the immune system is regulated becomes available.