Led by Professor David Hodson, at University of Oxford, Dr Ildem Akerman, at University of Birmingham, and Dr Johannes Broichhagen, at Leibniz FMP, this project will pioneer new approaches to make better beta cells ready for transplantation, protect the beta cells from an immune attack, and to regrow beta cells inside the pancreas. This research could speed up progress to making life-changing beta cell therapies available for people with type 1 diabetes.

Background to the research project

For people living with type 1 diabetes, a cure is likely to mean a combination of different treatments. We need to replace insulin-making beta cells that have been destroyed by the immune system, so people can start to make their own insulin again. And we need to protect new cells from an immune system that is primed to seek out and destroy them.

To reach this goal, scientists are pioneering methods to grow new beta cells in the lab and transplant them into people with type 1 diabetes. Scientists can do this using stem cells. Stem cells have the special ability to become just about any cell in the body, including beta cells. But at the moment, beta cells made from stem cells just aren’t as good at controlling blood sugar levels as real beta cells and don’t survive for long enough. Because of these challenges, scientists are also exploring treatments that could trigger new beta cells to regrow directly inside the pancreas.

Once we can give people with type 1 working beta cells, we also need to protect them from the type 1 immune attack. Treatments, called immunotherapies, are designed to do this by retraining the immune system.

Professor Hodson, Dr Akerman and Dr Broichhagen are hoping to make transformational progress in all three of these areas with the help of two molecules known as incretin receptors. These receptors are found on the surface of beta cells and act as on-off switches to help control the release of insulin. Scientists have already harnessed their potential and developed type 2 diabetes drugs that target the receptors, to help people lower their blood sugar levels. They think the receptors could be key to unlocking major progress in type 1 diabetes beta cell therapies too.

What will the team do in this project?

1. Produce better functioning and longer lasting beta cells made from stem cells.

The team has previously discovered that around 20% of lab-made beta cells have incretin receptors on their surface, and that these are better at producing insulin than beta cells without it.

First, the team will develop a way to find the cells that have the receptors, using a technique called cell sorting. If this method was used to analyse a smoothie it would be able to tell us what fruits were used to make it and locate them. Then to check how well they are working, they’ll transplant the receptor beta cells into mice with type 1 diabetes and test if they work better than beta cells without these receptors.

2. Deliver an immunotherapy straight to the surface of the beta cells, to help better shield them from an immune attack.

The team will design an immunotherapy that will seek out and bind to incretin receptors at the surface of beta cells, so the treatment goes straight to where it’s needed. They’ll investigate if this precision delivery makes the immunotherapy more effective at slowing or stopping an immune attack, and brings fewer side effects, in mice with type 1 diabetes.

3. Coax other cells in the pancreas, called alpha cells, to transform into beta cells.

Alpha cells produce a hormone that raises blood sugar and are left unharmed by the type 1 immune attack. They carry incretin receptors on their surface. The research team will modify existing drugs that target incretin receptors to carry cargo that works to change the identity of an alpha cell into a beta cell.

How will this research help people with type 1 diabetes?

Beta cells therapies have the potential to transform how we treat type 1 and to form part of a cure. Selecting for the top performing lab-made beta cells and arming them with a protective immunotherapy will be key in moving transplants from the lab towards the clinic. While enticing new beta cells to grow inside the body could give us another way of restoring people with type 1’s own insulin production.

Bringing back beta cells would allow us to say goodbye to insulin injections and pumps, reduce the need for constant blood sugar monitoring and help prevent diabetes complications.

Professor David Hodson said:

“During the past decade, a lot of our work has focused on insulin-boosting molecules found on beta cells, called incretin receptors, which have become major drug targets for type 2 diabetes and obesity therapy. Using our knowledge and innovative technologies, we will now translate our work in type 2 diabetes and leverage the potential of incretin receptors in the type 1 diabetes space.

“We’ve developed an ambitious three-prong research programme that spans beta cell replacement, protection and regeneration, so as to give us the best chance of driving discoveries that could make these treatments available for people living with type 1 diabetes.”

Professor Francesca Spagnoli and Dr Rocio Sancho at King’s College London, together with Professor Molly Stevens at University of Oxford, hope to unlock the full potential of transplants of insulin-making beta cells. They’ll innovate ways to keep cells safe from harm once they’re transplanted into someone with type 1, so we can move closer to the day when beta cell transplants can free people from the relentless task of managing type 1 diabetes.

Background to the research project

Scientists are using stem cells to develop treatments to replace the beta cells that have been destroyed in people living with type 1 diabetes. Stem cells have the special ability to shape-shift into other types of cells in the body, including beta cells.

Small clinical trials of stem cell-turned beta cell transplants are now underway and are showing early promise. But after being transplanted into people with type 1 diabetes, new beta cells struggle to survive and gradually lose their ability to make enough insulin and tightly control blood sugar levels.

Using expertise from different fields including biology, immunology and engineering Professor Spagnoli, Dr Sancho and Professor Stevens will lead a team to tackle these challenges and give lab-grown beta cells the tools they need to survive and do their job after transplant.

What will the team do in this project?

The team will explore ways to both create tougher beta cells that can better withstand their post-transplant environment, and to make this environment friendlier.

1. 1. They’ll replicate the supportive environment found in a healthy pancreas by coating their lab-grown beta cells with protective gels that can help them stay safe and strong.
   2. They’ll use nanoparticle technology to deliver ingredients that can give the cells a survival boost after transplantation and protect them from an immune system attack.
   3. They’ll develop a transplantation device that beta cells can live inside. This protective ‘cage’ will provide the cells with the right levels of oxygen they need to survive and make them more resistant to their hostile surroundings. They’ll transplant this device containing their reinforced beta cells into rats with type 1 diabetes to investigate if the cells manage to survive long-term and produce enough insulin to control blood sugar levels.

How will this research help people with type 1 diabetes?

Creating the ideal conditions that keep transplanted beta cells alive and kicking could help us move quicker towards a new era in type 1 diabetes, where people are free from the burden of taking insulin, the fear of hypos and complications, and the mental load of self-managing their blood sugar levels.

Professor Francesca Spagnoli said:

“The Type 1 Diabetes Grand Challenge funding means we can explore new avenues in diabetes research. We’ll be able to start moving some of our discoveries closer to clinical applications and drive improvements in cell replacement therapies, which could ultimately cure type 1 diabetes.”

Professor Shareen Forbes, at University of Edinburgh, and Dr Lisa White, at University of Nottingham are exploring better and more innovative ways to transplant islets, clusters of pancreas cells, into people with type 1 diabetes to enable them to make their own insulin. This could pave the way for wider use of this life-changing treatment, while also making islet transplants much more effective.

Background to the research project

In an islet transplant, clusters of cells (called islets) from a donor pancreas are transplanted into someone with type 1 diabetes and start to produce insulin. They’re currently offered to some people with type 1 diabetes who have severe hypos and no awareness of them. However, usually about 60% of the donor cells die soon after transplant.

This means lots of donor islets are needed to have an impact on blood sugar levels. But with a limited number of donor pancreases available for islet transplantation, very few people with type 1 diabetes can currently benefit.

What’s more, islet transplants aren’t as effective as they could be. They rarely allow people to produce enough insulin to stop insulin therapy. And people need to take anti-rejection drugs to prevent their bodies rejecting the donor cells, which can bring serious side-effects.

Scientists are looking at ways to improve the benefits and availability of islet transplants, so they can become part of a cure for type 1 diabetes. Professor Forbes and Dr White think drugs packaged inside microparticles could provide an answer. Microparticles are tiny particles that help to protect a drug from the harsh environment in the body and deliver it to exactly where it’s needed. If drugs that keep islets healthy and protect them from the immune system could be transplanted alongside islets, it could help them to survive and thrive for longer.

What will the team do in this project?

Professor Forbes and Dr White will package microparticles with immune-altering and other drugs to improve the survival of transplanted islets. They will test different combinations of drugs in islet transplants in mice, to see which work best to help islets survive and control blood sugar levels.

The team will then run experiments to investigate how to scale up the dose of the drugs and how the treatment might work in humans.

Finally, they will check if the most promising drug microparticle combinations also work to protect beta cells that have been grown in the lab from stem cells.

How will this research help people with type 1 diabetes?

At the moment only a tiny fraction of people living with type 1 diabetes are eligible for islet transplants. And they’re far from a permanent or perfect fix.

If the team can improve the survival of donor islets it could unleash the benefits of islets transplants – making them much more effective at managing blood sugar levels, eliminating the need for anti-rejection drugs and opening them up for more people with type 1 diabetes.

In the longer-term, their discoveries could also be used to radically improve transplants of lab-made beta cells. This would entirely remove the supply problem of using donor cells, so that in the future everyone with type 1 diabetes could benefit from transplants.

Professor Shareen Forbes said:

“I hope the Grand Challenge’s investment will give people living with type 1 diabetes hope that a cure can be achieved in their lifetime.

“The funding has allowed scientists from diverse fields to come together in this project with a common goal of doing some truly innovative research that will advance the field. By improving the benefits of human pancreas cell transplants, and in time transplants using stem cells, we hope to contribute towards a future where people with type 1 diabetes can live a life free from insulin injections.”

Professor Shanta Persaud and Dr Aileen King are world-leading experts at studying how insulin-producing beta cells work and develop in humans. They’ll use their specialised knowledge to run state-of-the-art experiments and find ways to improve methods to engineer new beta cells in the lab, so they act and react more like real human beta cells. This project could help to accelerate progress towards life-changing new treatments that restore insulin production in people with type 1 and bring us closer to a cell-based cure for the condition.

Background to the research project

People with type 1 diabetes rely on insulin injections or pumps to replace what the immune system has destroyed. While insulin therapy is lifesaving, current insulins don’t come close to the minute-to-minute adjustments that beta cells make to manage blood sugar levels.

Scientists have been trying to find ways to give people with type 1 new beta cells, by making them in the lab from stem cells and transplanting them inside the body. Although lots of progress has been made in recent years, lab-made cells just aren’t as good at producing insulin or responding to changing blood sugar levels as real beta cells are.

Lots of what we know about turning stem cells into beta cells is based on how beta cells develop in mice. But Professor Persaud and Dr King have been studying human pancreas development and want to harness this knowledge to make better performing beta cells that are well equipped to survive transplantation.

What will the team do in this project?

Professor Persaud and Dr King will lead a team to:

1. Improve the process of turning stem cells into beta cells.

They’ve discovered that cells that support nerve cells (called Schwann cells) may also help support beta cells. They will carry out tests to see if Schwann cells could improve the ability of stem cells to transform into functioning beta cells.

2. Make sure lab-grown beta cells produce the right amount of insulin.

Once beta cells have been made, the team must make sure they are an elite class of insulin producers. They’ll run tests to see what type of support, nutrients and special molecules can help the newly made cells work even better.

Next, they’ll use state-of-the-art techniques to rigorously test if the lab-made beta cells are really acting like real beta cells. This includes looking at how the lab-made beta cells use oxygen, store insulin and respond to rising blood sugar levels.

3. Give lab-grown beta cells the best chance of surviving after transplantation.

The team will coat clusters of lab-grown beta cells with survival boosting molecules, by a process called nanoencapsulation, and test if this helps them survive transplantation better.

How will this research help people with type 1 diabetes?

Having an unlimited supply of elite beta cells ready for transplantation could mean a future where people with type 1 diabetes never have to think about their blood sugar levels or insulin, because their beta cells are doing it for them. While transplants would also help to reduce the risk of developing diabetes complications.

If successful, this project will turbo charge progress towards clinical trials of transplants using new and improved lab-grown lab cells, and move us closer to a cure.

Dr Aileen King said:

“People with type 1 diabetes have to constantly think about their blood glucose levels and adjust their insulin doses in response. Our aspiration is to produce fully functioning beta cells suitable to implant into people living with type 1 diabetes, which do this on their behalf.

“This would be transformative for people with the condition, as it would restore the body’s minute-to-minute insulin production that is required to carefully control blood glucose levels – reducing the risk of dangerous blood sugar lows and long-term diabetes complications, while also reducing the huge psychological impact of living with diabetes.”