Objective
This research project will refine our lipid nanoparticle technology, by optimizing key parameters to achieve robust immune protection of beta cells with minimal impact on other immune functions, with the objective to ready this as a therapeutic for testing in clinical trials in people living with T1D.
Background Rationale
Finding a way to stop T cells from attacking beta-cells would treat the underlying cause of T1D. A way to stop the immune attack would allow beta cells, transplanted into people living with T1D, to survive and avoid destruction. Moreover, if the immune system can be stopped early enough, a person’s own beta cells can be spared and diabetes would never develop in the first place. The challenge to this approach is finding a way to stop the T cells from attacking beta cells, without shutting down the whole immune system. Many immune suppression drugs could stop the attack on beta cells, but also impair the whole immune system which carries too much risk to be an appropriate treatment for most vulnerable people living with T1D. Thus, a treatment that can stop the inappropriate immune attack on beta-cells but leave all other important immune functions intact would be a safe and potentially curative therapy for T1D.
Scientists have attempted to develop something that does this for over two decades now, but with limited success. Most attempts have used synthetic peptides that mimic a person’s beta-cell proteins, and administered them in various forms in an attempt to desensitize the immune system to beta cells. Unfortunately, numerous studies over the years have revealed that this is not a strong enough signal to re-educate the immune system long-term. The recent clinical advancement of mRNA vaccines has opened the door to new technological advancements in therapeutics using lipid nanoparticles. Lipid nanoparticles are fat droplets that can shuttle therapeutics safely throughout the circulatory system and deliver them with high efficiency to APCs of the immune system. With many years of expertise in nanoparticles, our team has developed a new multi-cargo lipid nanoparticle technology, that can deliver both mRNA and immune-modulating drugs to APCs following a simple injection. By encapsulating both mRNA to encode for beta cell proteins, and drugs that act as signals to stop T cells, our multi-cargo lipid nanoparticles can essentially retrain the immune system in T1D to stop attacking beta cells, while keeping other essential immune functions intact. We have already shown that our multi-cargo lipid nanoparticle system prevents diabetes and spares the beta cells from immune attack in a mouse model of T1D. The effect was robust and lasted for approximately 15 weeks after injection in mice. We hypothesize that this could be an effective therapeutic for T1D, that could delay or reverse autoimmune attack in T1D with an single injection every few months
Description of Project
Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing beta cells of the pancreas. The cells that orchestrate this attack are immune cells, namely antigen presenting cells (APCs) and T cells. APCs constantly surveil the body by taking up proteins, presenting them to T cells and providing signals to T cells that instruct it on how to react to the protein. If a T cell recognizes the protein, but the APC signals that it is safe and does not need to be dealt with, a T cell will ignore that protein. In contrast, if a T cell recognizes the protein, and the APC signals that it is a threat, the T cell will mount an attack on anything containing that protein. In the case of T1D, T cells inappropriately attack proteins found in beta cells, resulting in their destruction, the loss of insulin, and consequently the loss of blood sugar control. Finding a way to stop T cells from attacking beta-cells would treat the underlying cause of T1D.
Our research aims to use a new and innovative technology to precisely stop the inappropriate immune attack of beta cells, without shutting down other important immune functions. Our technology uses lipid nanoparticles, which are essentially droplets of fat, that can shuttle signals through the blood and directly to APCs which can then re-educate T cells. Two signals inside the lipid nanoparticle are needed for this re-education: 1) mRNA that encodes beta-cell proteins and 2) molecules that act as immune stop signals. APCs take up these lipid nanoparticles following an injection, and present both the expressed beta-cell protein and the stop signals simultaneously to offending T cells. This instructs the T cells to stop attacking beta-cell proteins, but does not impact T cells that respond to other types of foreign and dangerous proteins, like virus particles.
Our early research has shown that our lipid nanoparticle works in mouse models of T1D, effectively stopping their immune system from attacking beta cells and preventing diabetes. This research proposal will further refine this lipid nanoparticle technology, bringing us closer to testing in clinical trials and our ultimate goal of developing a treatment that prevent or reverse the inappropriate autoimmune attack and improve the lives of people living with T1D.
Anticipated Outcome
In this research project we will test key design parameters of our multi-cargo lipid nanoparticle to maximize its efficacy with the goal of refining the formulation to test in clinical trials. We will test parameters related to antigen design, immune-modulating drug composition, and dosing regimen. In addition, while we have shown that we can prevent autoimmunity in a mouse model of T1D, this research will test whether we can reverse autoimmunity in mice with established diabetes. At the end of this research project, we anticipate having a refined and optimized lipid nanoparticle formulation, that is effective in both preventing and reversing autoimmunity in a robust and durable manner. This work will support and accelerate efforts toward clinical trials in T1D.
Relevance to T1D
The field has long been trying to solve the challenge of stopping beta cell autoimmunity in T1D without broad immune suppression. The current research proposal will optimize a new mRNA lipid nanoparticle-enabled therapeutic strategy that effectively prevents autoimmunity in a mouse model of T1D, with the goal of translating this research to clinical trials in people. This could potentially result in a first of its kind curative therapeutic, that can safely and effectively treat or prevent autoimmune-attack of beta cells and ultimately improve the lives of people at risk of or living with T1D.