Diabetes breakthrough

UTS researchers have identified molecules secreted by a parasitic worm that prevent the development of Type 1 diabetes in mice. A commercial version of the product is currently being developed for use in humans.

Sheila Donnelly, photo by Joanne Saad

The finding, which has huge implications for the treatment of diabetes and other autoimmune diseases, came about by chance. Former Director of the Institute for the Biotechnology of Infectious Diseases (IBID) John P. Dalton and UTS researchers Sheila Donnelly and Bronwyn O’Brien were chatting about their research over coffee.

For many years, Dalton and Donnelly – a researcher in the Infection, Immunity and Innovation (i3) Institute, formerly IBID – have been working with a parasitic worm called Fasciola hepatica.

The parasite is a flatworm that lodges itself in the livers of cattle and sheep, causing the disease fasciolosis. Traditionally regarded as a disease of livestock, fasciolosis has emerged as an important human disease. Up to 17 million people are believed to be infected worldwide.

John P. Dalton

Dalton’s and Donnelly’s investigations focused on how Fasciola hepatica was regulating the immune response of its host. “In particular, we were looking at how the parasite was manipulating a specific immune cell, called the macrophage,” says Donnelly.

“It appeared that it was secreting molecules that were switching off the macrophage and this regulated the immune response.”  

At the same time, O’Brien (from the School of Medical and Molecular Biosciences) was researching the immune responses involved in the development of Type 1 diabetes. This autoimmune disease causes insulin-secreting beta cells within the pancreas to be destroyed by the body’s immune system. 

Using a model of Type 1 diabetes known as the NOD (non-obese diabetic) mouse, O’Brien was trying to determine why the macrophages in these mice were over activated and why they destroyed the pancreatic beta cells.

O’Brien says, “I remember having a few cups of coffee with John and Sheila saying that in Type 1 diabetes you get a lot of inflammation. Immune cells like macrophages are being potently activated and aggressively attack the beta cells. If there are no beta cells, there’s no insulin and you get Type 1 diabetes.”

The trio decided to team-up on a collaborative research project.

Dalton and Donnelly extracted the parasite from the livers of sheep and collected the worms’ secretions. O’Brien and Donnelly then treated the NOD mice with the secretions and observed them for six months to see if they developed diabetes.

“We were not really expecting much at this point,” says O’Brien. “However, the results were surprising. I said, ‘My goodness Sheila, the parasite secretions are stopping Type 1 diabetes’.”

Though it was a substantial finding, the group needed to identify which specific molecules from the mix of parasite secretions were protecting the mice from disease.

Worm therapy, which uses parasitic worms to treat autoimmune disease, is increasingly being recognised and applied. “In humans, researchers use parasites to treat inflammatory bowel disease and they also found that if people with multiple sclerosis have become infected with parasitic worms, their symptoms actually subside,” says O’Brien.

“Humans infected with parasitic worms don’t develop diseases mediated by an overactive immune response (autoimmune disease) like Type 1 diabetes,” adds Donnelly.

“But for us to offer infection with a parasitic worm to a child suffering from Type 1 diabetes is inappropriate because many of these worms cause disease. Our idea was to harness the molecules these worms are secreting and find out if they have the ability to mimic the parasite infection without any associated side effects.”

According to O’Brien, working at the molecular level in worm therapy is a new frontier. “Not much progress has been made in terms of the holy grail, which is the identification of the actual protective molecules secreted by worms.”

That is, until now.

Bronwyn O'Brien and Mark Robinson, photo by Joanne Saad

Mark Robinson, a UTS Chancellor’s Postdoctoral Fellow with the research group, says, “Identifying the bio-active molecules was a significant step forward.”

He uses a technique known as proteomics (the study of proteins) to characterise the molecules secreted by parasitic worms. Robinson applied this to Fasciola hepatica.

“By adding individual Fasciola molecules to macrophage cells in culture and watching how the cells respond, we could identify the parasite molecules that inactivated the macrophages.”

Robinson says, “The initial screening identified a number of molecules that would potentially protect against Type 1 diabetes.”

O’Brien and Donnelly then repeated their initial test with the mice by injecting them with the molecules. “The results were identical,” says O’Brien. Type 1 diabetes was again prevented.

Of the specific, identified molecules, one is completely novel and a provisional patent application has been filed.

“At the moment we’re testing different combinations of the molecules and determining which treatment regimes work best,” says O’Brien.

The researchers are also looking at conducting experiments with mice that intervene much later in the disease. “We want to know how long we can wait before the treatment is no longer effective,” O’Brien says.

Last year, in preparation for human trials, Andrew Hutchinson, a UTS Chancellor’s Postdoctoral Fellow, became involved in the project. His role is to look at human immune responses.

O’Brien says, “We need evidence that what we’ve observed in the mice translates to humans.”

Hutchinson says it’s a huge step forward. “We are now trying to get support data to take this concept into pre-clinical development in humans in the next few years.”

The team will also test if the Fasciola hepatica molecules can prevent rejection of pancreatic islet transplants. These transplants involve clusters of insulin-producing beta cells (the islets) being implanted into a patient with Type 1 diabetes in order to restore insulin secretion and reverse diabetes.

“The immune system of diabetic patients is very aggressive,” says Donnelly. “The transplants are quickly rejected unless lifelong immunosuppressive drugs are given to the patients.” 

Andrew Hutchinson, photo by Katia Sanfilippo

However, Hutchinson adds, “Immunosuppressive drugs, used to stop rejection of islet transplants, have a number of detrimental side effects.

“We’re aiming at a short treatment of parasite antigens that will regulate the activity of the immune response and stop transplant rejection. It would be a phenomenal breakthrough if it was able to do both without patients also needing long-term immune suppression.”
 
It’s hoped the molecules may also stop rejection in solid organ transplants, like livers.

In the meantime, UniQuest’s Manager of Innovation and Commercial Development Pamela Blaikie is helping the team commercialise the treatment for Type 1 diabetes.

“We are hoping to either licence it out to a biotechnology or pharmaceutical company or to form our own start-up company,” says Hutchinson.

The group was recently awarded a prestigious National Health and Medical Research Council grant to fund further proof-of-concept studies.

The researchers say they were lucky in that their combination of complementary expertise enabled them to unravel the mixture of molecules released by Fasciola hepatica to a relatively simple cocktail. But, O’Brien says, as it has been noted before, “Good science is a mixture of serendipity and astute observation.”