Objective
In type 1 diabetes (T1D), the insulin-producing cells in the pancreas, β cells, are destroyed by immune cells that mistake them as foreign pathogens. One way T1D progression begins is when self-reactive immune cells infiltrate and surround pancreatic islets, where β cells are located. This immune infiltration is the result of communication between the pancreatic islet cells and immune cells: islets produce proteins, called chemokines, that attract immune cells, and the immune cells contain receptors that bind to chemokines and lead them into the islets. Both processes will likely need to be blocked to completely prevent self-reactive immune cells from entering islets and destroying β cells. Further, once immune cells begin infiltrating islets, which they usually have at the time of diagnosis, it is very difficult to prevent more from coming in and the immune cells that have already infiltrated the islets will remain.
Fortunately, not all immune cells that infiltrate islets are bad. One class of cells, called regulatory T cells (Tregs), prevent self-reactive cells from destroying healthy cells like β cells. In T1D, however, there is an imbalance between Tregs and self-reactive cells, and β cell destruction takes place. The goal of this proposal is to send more Tregs into the islets to counter the destructive immune cells and halt β cell loss.
We will achieve this goal by developing new therapies that target both sides of the immune cell migration process: the immune cells themselves and the pancreatic islet cells. To accomplish this, we will use technology developed in our labs in which genetic material (messenger RNA, mRNA) is delivered to either Tregs or islet cells by lipid (fat-like) materials that are similar to the lipids naturally found in our cell membranes, the cells’ outer layer. When these lipids are mixed with genetic material, they assemble into spheres that are approximately 1,000 times smaller than the width of a human hair. These spheres, which are called lipid nanoparticles, enter cells and deliver their cargo safely and effectively.
In the first objective, we will use lipid nanoparticles we have developed that only deliver mRNA to Tregs while avoiding other immune cells. The mRNA delivered by the lipid nanoparticles will instruct the Tregs to make proteins that attract them to islet cells. At the same time, we will use lipid nanoparticles we have developed that only deliver mRNA to islet cells to instruct the islet cells to make proteins that attract Tregs and to stop making proteins that attract self-reactive immune cells. By combining these two approaches, we will achieve our goal of preventing self-reactive immune cells from destroying β cells, halting the progression of T1D.
Background Rationale
Autoimmunity occurs when the immune system attacks and damages the body in unwanted ways. Normally, regulatory immune cells prevent autoimmunity by subduing immune responses to oneself. In some people, it is thought that the immune system will begin to attack insulin-producing β cells in the islets of the pancreas, but regulatory cells fail to protect β cells from the immune system. This leads to immune cells eliminating β cells, a lack of insulin production, and subsequent diabetes. Some T1D therapies aim to stop the immune system from attacking β cells, but these therapies inhibit the entire immune system, which protects from pathogens or other malignancies. Other therapies have tried boosting regulatory cells to be more active in the pancreas, but thus far all these therapies do not protect β cells. The ideal therapy would promote protective regulatory cells to traffic to the islets, and prevent damaging immune cells from going to islets, while not modulating other cell types.
Description of Project
n some people, the immune system will attack and eliminate insulin producing cells, also known as β cells, within the islets of the pancreas. In time, this leads to diabetes, or a loss of insulin production that results in high levels of blood glucose, which can have devastating consequences for those affected. However, the immune system can also control this activity through what are called regulatory cells. In type 1 diabetes (T1D), these regulatory cells become lost or inactive, allowing the immune system to cause disease. The goal of this application is two fold. First, we will boost the ability of regulatory cells to enter pancreatic islets and help to control the development of disease. Second, we will make the islets themselves promote regulatory cells and reduce the ability of the immune system to cause disease. We will achieve this using a similar strategy to the messenger RNA - lipid nanoparticle (mRNA-LNP) vaccine for COVID. Using specially formulated mRNA-LNPs as a gene therapy strategy, we will target regulatory cells to provide them with a stronger ability to go to the pancreas and prevent disease. We will use the same strategy to target the pancreas, providing the islets with a greater ability to attract regulatory cells while at the same time reducing their ability to attract pathogenic immune responses. By boosting the regulatory responses, and reducing the pathogenic responses, we will return the pancreas to a more balanced state that will slow or stop diabetes progression. The use of mRNA-LNPs will limit broad effects on the body that can make other therapies less tolerable. By using the safe and effective mRNA-LNP platform, we hope that the strategies in this proposal can improve the lives of people living with Type-1 diabetes.
Anticipated Outcome
We anticipate that mRNA-LNPs targeting regulatory cells will successfully boost regulatory cell migration towards islet cells and become active upon encountering islet cells. Importantly, these effects will be specific to regulatory cells and will not impact other immune cells. It is expected that mRNA-LNPs targeting islet cells will cause islet cells to attract beneficial regulatory cells while not attracting damaging immune cells. This effect is expected to be specific to islet cells and not other cell types. These strategies are expected to work in simple cell assays. Further, use of these mRNA-LNPs are anticipated to prevent diabetes in more complex diabetes model systems.
Relevance to T1D
Type 1 Diabetes (T1D) occurs when otherwise healthy individuals, the majority of which are children or young adults, have an unknown pre-disposition that drives the immune system to attack β cells in an autoimmune response. Ideally, therapies that inhibit this autoimmune response would be employed to slow down or halt β cell destruction. Currently, the only FDA approved treatment that suppresses the T1D autoimmune response can delay diabetes onset but can have side effects that potentially weakens the immune system’s response to pathogens or other pathologies. An ideal treatment would not cause broad suppression of the immune system, and it would be specific to pancreas tissues and immune cells involved in the autoimmune response. Our proposed mRNA-LNP strategy will simultaneously enhance the ability of the immune system to regulate autoimmune activity against islet cells and reduce the ability of the pathogenic immune responses to access pancreatic islets. Our strategy leverages a globally employed clinically approved vaccine platform to create a novel therapeutic approach to curing Type 1 diabetes.