Objective
We have identified a molecule which can keep human beta-cells healthy. To understand its true potential for treating T1DM we need to further understand how it acts and improve its ability to activate receptors selectively in the islet. This will enhance its efficacy and reduce potential side effects.
Our specific aims are to:
1. Determine which cells within the islet have our receptor of interest.
2. Determine how our molecule functions to keep beta-cells healthy.
3. Develop a molecule that more specifically targets the islet.
Background Rationale
A key therapeutic approach for the treatment of type 1 diabetes is the prevention of beta-cell death either by directly keeping them healthy or by preventing beta-cell attack by immune cells. The aim of this being to halt disease progression and maintain blood sugar control. The hope would be to reduce the amount of insulin therapy required or to remove it altogether. There are currently no licensed drugs which try to achieve these goals. Our previous work identified an islet receptor which has the potential to achieve these aims. Activation of this receptor powerfully protects human islets from damage, does not inhibit insulin release and may reduce the ability of immune cells to recognise islets. We have identified a molecule which selectively activates this receptor that can keep human beta cells healthy. The task now is to further understand how it works and to develop this molecule so that it more selectively activates receptors in the islet, by doing so we will develop a molecule that hopefully could be translated towards treating T1DM.
Description of Project
Specialised cells, called beta-cells, found in islets of the pancreas, have the important task of regulating blood sugar levels. This is achieved by their release of a hormone called insulin which helps the body use the sugar in our diet for energy. In Type 1 diabetes (T1DM) a person’s own immune system kills their beta-cells. If untreated blood sugar levels become abnormally elevated. In the long-term this damages all organs of the body and causes ill health. The only treatment for T1DM is to replace the lost insulin by either daily self-administered injections or continuous delivery via a pump. This controls blood sugar levels, but does not cure T1DM, because the patient’s immune destruction of their beta-cells is not prevented, or the damaged beta-cells restored.
Generally, experimental approaches to treat T1DM have focused on suppressing the immune attack on beta-cells. However, strategies which help maintain enough healthy beta-cells, so blood sugar can be better controlled, are also required. This could be achieved by protecting beta-cells from damage, increasing their number and or hiding them from immune destruction, with the aim of reducing or removing the need for self-administration of insulin.
Our previous work showed activating a specific receptor found in islets protects beta-cells from the damaging chemicals present during T1DM immune attack and may hide beta-cells from being recognised by the immune system. However, this receptor is also found in the brain and its activation in this organ would be undesirable. Our current project aims to more fully understand how activation of this receptor helps maintain beta-cell health and to develop a molecule that targets these receptors in the islet rather than the brain
Anticipated Outcome
If successful, this project will have identified a novel drug which selectively targets the islet to help maintain beta-cell health and hopefully has the potential to treat Type 1 Diabetes. This molecule may have the potential to protect beta-cells from damage, hide them from the immune system and could improve blood sugar control in people with Type 1 diabetes. This would ultimately lower the exogenous insulin burden and likely reduce hypoglycaemic events but may also have utility in halting or delaying progression of T1DM. Having validated our molecule in mouse and human tissues, and in animal models of disease, the results will represent a significant step along the road to clinical translation. A key next step for us would be to design clinical trials to evaluate safety and efficacy.
Relevance to T1D
Our proposal is highly relevant to type 1 diabetes. A significant unmet clinical need is a treatment for people with existing diabetes that aims to achieve reinstatement of a relatively healthy population of beta-cells either by protecting them from damage, making remnant beta-cells function more efficiently and/or increasing their number. Recent clinical trial data has provided proof of principle that these types of approach can lower self-administration of insulin and reduce the risk of hypoglycaemic episodes making T1DM treatment more manageable and less dangerous. Deploying such agents in those with early diagnosis may also stop or delay disease progression. Our hope is to develop a novel drug candidate for maintaining a healthier beta-cell population in T1DM, which can be developed quickly towards clinic.