Professor Eoin McKinney and his team at University of Cambridge have discovered ‘signatures’ of immune cell changes seen only in people who later develop type 1 diabetes. In this Type 1 Diabetes Grand Challenge project, they will search for existing medicines that can rewrite this signature to prevent type 1 diabetes.

Background to the research project

Understanding how type 1 diabetes develops is vital for preventing the condition. Researchers are looking at the biological processes that lead to the immune system dysfunction in type 1 diabetes and ways to block or reverse these.

Mapping signatures of cell changes

One scientist working on this is Professor Eoin McKinney, with funding from the Type 1 Diabetes Grand Challenge. His team has used machine learning to analyse signatures in cell samples from hundreds of people who went on to develop type 1 diabetes. These signatures show patterns of changes in immune cells, which are linked to the development of type 1 diabetes.

There are also similar signatures that show how cells in the body are changed by drugs. There are large data banks of these drug signatures for the many thousands of medicines prescribed for all sorts of conditions. Professor McKinney will use this vast library of drug signatures to search for a way to reverse the changes to the immune system that lead to type 1 diabetes.

What will Professor McKinney do in this project?

The researchers will hunt for matches between the type 1 diabetes signatures they’ve discovered and the drug signatures that have been mapped for individual medicines. When they find a pattern in a drug signature that complements a pattern in their type 1 signature, the medicine has the potential – in theory – to reverse the changes and prevent the condition.

Professor McKinney said: “By collaborating with international groups, we have generated detailed maps of immune cell changes occurring from the earliest stages of T1D through to diagnosis. Now, we plan to use that information to find new treatments that might prevent progression, by matching changes seen before type 1 diabetes to those produced by commonly used medicines. By finding a match, we hope to identify which drugs might be most easily used to reverse or stop disease progression.”

Moving from theory to reality

Professor McKinney will then check if the drugs work in practice by examining how they change immune responses. First in human cells and then in mice, gathering as much information as possible about each drug. This means that when it comes to testing in people, only medicines with the highest chance of success will make the cut.

Rapid progress is possible

The team expects to have a candidate medicine ready to give to people at high risk of type 1 diabetes in a prevention trial much faster than usual. This is because this medicine would have already been through extensive safety testing for its original use. So, if the lab tests are positive, there shouldn’t be anything standing in the way of a clinical trial.

How will this research help people with type 1 diabetes?

The first signs of type 1 immune attack can be detected years before symptoms develop. Finding a medicine that can fend off the condition will give people the chance to protect themselves for longer. And by using an existing medicine – rather than developing a new drug – this breakthrough could come years or decades sooner.

Professor McKinney said: “By selecting candidate treatments rationally based on a match with type 1 data, we will stand the best possible chance of finding a safe and effective approach to stop the condition with real impact for patients everywhere.”

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.”

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.”

Take part in this research project

James is recruiting people 18-70 living with type 1 diabetes who can attend the University Hospital of Wales, Cardiff. Taking part would involve giving two blood samples, one in the morning between 7-9am and another 10-14 hours later, at the University Hospital of Wales, Cardiff. Eligible participants who successfully donate both samples will be provided with a £300 voucher from Lovetoshop.

To get involved in this study, please contact the research nurses for further information: Shinto Jose (joses8@cardiff.ac.uk) and Alex Howell (howella4@cardiff.ac.uk).