Root causes

Combination therapy could help protect insulin-producing beta cells

Dr Danijela Tatovic’s Root Causes Programme Grant project

Dr Danijela Tatovic

Dr Danijela Tatovic is a clinical research fellow at Cardiff University who designs early phase clinical trials, which are an important step towards taking science from the lab bench into the clinic. In this Grand Challenge research project, Dr Tatovic will test a combination of two therapies, both already licensed to treat other autoimmune conditions, to see if together, they can help protect surviving beta cells and delay progression of type 1.

Background to the research project

Type 1 diabetes occurs when a person’s own immune system mistakenly attacks insulin-producing beta cells in the pancreas. This process is known as an autoimmune response and in people at risk of type 1, it begins long before the symptoms of diabetes appear.

New therapies that help to control these autoimmune responses and prevent or slow the attack on beta cells are showing real promise. One medicine, abatacept helps to stop ‘bad’ immune cells from attacking the beta cells. However, the drug also dampens down ‘good’ immune cells that naturally control the autoimmune response. So, it’s important we have the right balance of them.

Dr Danijela Tatovic’s research is exploring how to overcome this problem. So far, she has shown that in mice with type 1 combining abatacept with another medicine, called IL-2, can help to keep the right balance of immune cells, so beta cells are better protected from the ‘bad’ ones.

What will Dr Danijela Tatovic do in this project?

Now Dr Tatovic’s’s team wants to understand whether a combination of abatacept and IL-2 works in people with type 1 and to find out what dose and timings of the medicines work best.

The researchers will run a small clinical trial where one group of people with type 1 will receive abatacept over two months, boosted with IL-2. Another group will receive abatacept alone.

To understand more about how the immune cells respond to the medication, the researchers will use state-of-the-art methods and equipment to track where the immune cells are in the body, and when and how they are doing their job.

Dr Tatovic’s is also joining forces with other experts, who will  sophisticated mathematical models to analyse the data they collect and to predict which doses of each treatment is likely to be most successful in combination.

How will this research help people with type 1 diabetes?

Knowing which doses of the combination of drugs are most effective at preserving beta cells will allow the researchers to design a larger clinical trial, involving more people. The next trial will help them to find out whether the therapy can protect beta cells from destruction and prevent or slow progress of type 1 diabetes. In future, it could mean that people at risk of type 1 can be treated before their beta cells have been destroyed, to try to delay or prevent the condition from developing. While disrupting the immune attack in people who’ve just been diagnosed with type 1 could help to keep more of their surviving beta cells alive, so they can make some of their own insulin for longer.

Dr Danijela Tatovic said:

“As a clinical diabetologist, I witness the struggle that people with type 1 diabetes go through on a daily basis to achieve optimal control of their blood sugars. This is changing. We are on the cusp of making fundamental difference to the treatment of type 1 diabetes, from burdensome insulin replacement to preserving a person’s own insulin. I am delighted and very grateful to the Type 1 Diabetes Grand Challenge.”

Root causes

Does timing matter for therapies to prevent beta cell destruction?

Dr James Pearson’s Root Causes Programme Grant project

Dr James Pearson is a diabetes researcher at Cardiff University. This Grand Challenge project will allow him to test whether a new medicine, that slows the destruction of beta cells in people with type 1 diabetes, is more effective if administered at a particular time of day.

Background to the research project

Type 1 diabetes occurs when a person’s insulin-producing beta cells in the pancreas are destroyed mistakenly by the body’s own immune system. The error occurs, at least in part, because immune cells called Tregs that normally help prevent beta destruction, can’t do their job properly in people who develop type 1.

Medicines designed to help boost Tregs and protect beta cells from destruction are being tested in clinical trials with people who’ve recently been diagnosed with type 1. One of the medicines is a low dose of a protein called IL-2 that helps the population of Tregs grow and do their job effectively. However, although the trial results are promising, for some people, the medicine just doesn’t work.

Dr Pearson’s previous research tells us that the number of Tregs in a person’s blood follows a daily pattern, rising and falling during a single day. He’s also found that these cells can only do their job of policing the damaging immune responses at the root of type 1 at certain times of day. In mice, IL-2 protein is responsible for altering these time-of-day changes in Tregs. When the mice are given IL-2 at 7pm, their Tregs do a better job at preventing beta cell destruction than when the same dose is given at 7am.

What will Dr James Pearson do in this project?

Dr Pearson wants to find out whether the differences in Treg activity in the morning and evening can explain why some people with type 1 don’t benefit from the IL-2 therapy. He will explore when during the day Tregs get the biggest boost from the IL-2 in mice, and test whether IL-2 is more effective in the morning or evening at preventing or slowing type 1.

Dr Pearson will also study blood samples from people with type 1 to identify how the Treg activity varies between individuals. He will treat samples of people’s Tregs in the lab with IL-2 to see how it boosts the cells’ ability to control the immune cells that destroy beta cells.

How will this research help people with type 1 diabetes?

By looking closely at Treg cells in both mice and humans, Dr Pearson and his team will discover why Tregs behave differently at different times-of-day and the best time to give a promising new medicine to best boost Tregs, so they can to do their job better and help to fend off the immune attack in people with or at risk of type 1.

Dr Pearson’s research could mean that in future, IL-2 can be given to coincide with when the body’s cells are most responsive to the therapy. It may lead to a new clinical trial to test a time-of-day-specific low dose IL-2 for people with type 1 and those at high risk of developing the condition.

Dr James Pearson said:

“I am thrilled to receive this funding for our research which will expand our research group and move our research forward into clinical practice. This research will identify how immune cells vary over the course of the day but also how well they respond to therapy. This knowledge will enable us to improve the success of therapies for people with, and at risk of, type 1 diabetes by identifying when best to administer therapy.”