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?
- 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.
- 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.
- 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.”