Objective
The primary objective of this research is to validate the Islet Vascularized Micro-Organ (Islet-VMO) as a reproducible, human-relevant tool for studying Type 1 Diabetes (T1D) and evaluating new potential therapies. T1D is caused by the immune system mistakenly destroying the insulin-producing cells of the pancreas. While research has advanced considerably, scientists still lack practical, human-relevant tools for studying the earliest stages of this process, particularly how immune cells interact with blood vessels in the pancreas – a process that is quite different in human compared to mice. This is a critical gap, because blood vessels appear to play an active, not passive, role in directing the immune attack. The Islet-VMO is a small, engineered device containing living human blood vessel cells alongside insulin-producing cells derived from stem cells — together forming a miniature version of the pancreatic environment where T1D begins. Because it is built from human cells, it can capture biological processes that animal models miss, making it far more relevant to what actually happens in T1D patients. The goal of this project is to confirm that this model behaves the same way as real human pancreatic tissue in T1D patients. We will compare behavior of cells in our model to data from actual T1D patients, both under baseline conditions and during inflammation mimicking early disease. Once validated, we will use the model to test whether blocking specific molecules on blood vessel cells can reduce the infiltration of harmful immune cells and protect insulin-producing cells. This will demonstrate that the Islet-VMO is not only a valid representation of human T1D biology, but also a practical tool for identifying and evaluating new therapeutic targets.
In summary, this project aims to deliver a platform that can: 1) Accurately replicate the biology of early-stage human T1D; 2) identify new drug targets by testing interventions in a human-relevant system; 3) Reduce reliance on animal models that poorly predict human outcomes; and, 4) Meet FDA standards for human-relevant preclinical testing. In short, this research is about proving the value of a newly-developed tool that we hope can meaningfully accelerate the path to effective treatments for T1D.
Background Rationale
Type 1 Diabetes (T1D) is a serious, lifelong autoimmune disease in which the body's immune system mistakenly attacks and destroys the insulin-producing beta cells of the pancreas. Without these cells, the body cannot regulate blood sugar, and patients must depend on insulin therapy for survival. Despite 50 years of research, there is still no cure, and many fundamental questions remain, including exactly how and when this immune-driven destruction begins. Most of what we know about T1D has come from studies in specially bred laboratory mice. These animals develop a condition that resembles human T1D, and they have been invaluable for early research. However, mice and humans have meaningful biological differences that limit how much these findings can tell us about human disease. One of the most significant involves the cells that line blood vessels, called endothelial cells. In humans, endothelial cells are active participants in immune responses. When they sense inflammation, which is a hallmark of early T1D, they display specific molecular signals that can directly recruit and activate memory CD4+ T cells: a class of immune cells central to beta cell destruction. Critically, mouse endothelial cells do not behave this way and so a potentially key process in disease progression cannot be adequately studied in mouse models. This biological gap between mice and humans is one reason the FDA has begun actively encouraging researchers to develop new, human-relevant laboratory testing methods. These New Approach Methodologies (NAMs) will hopefully better predict whether treatments will work in people. Indeed, this is the gap our research addresses. Our team has developed the Islet-VMO: a miniature, engineered system that integrates living human blood vessels with stem cell-derived insulin-producing tissue. It is specifically designed to model the vascular and immune interactions at the heart of T1D pathology, and in a human context that animal studies cannot provide. The rationale for this research is clear: by rigorously validating the Islet-VMO against real patient data and demonstrating its ability to detect the effects of therapeutic interventions, we will establish a powerful new tool for studying T1D, one that is more biologically accurate, more ethically sound, and ultimately more likely to yield treatments that work in people.
Description of Project
Type 1 Diabetes (T1D) is a disease in which the body's own immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas. While scientists have known this for over 50 years, many fundamental questions remain unanswered, including exactly how and when this self-destruction begins. Most importantly, there are currently no treatments that stop disease. Much of what we know comes from studies in laboratory mice. While useful, mice differ from humans in important ways, particularly in how blood vessel cells behave during immune attacks. This may explain why many therapies that work in mice repeatedly fail in humans. In response to these concerns, our team has developed the Islet Vascularized Micro-Organ (Islet-VMO): a miniature, human cell-based laboratory model that recreates the environment inside the human pancreas, including its blood vessels and insulin-producing tissue. Because it uses living human cells, it can capture biological processes that animal models cannot. In this project, we will test whether the Islet-VMO accurately reflects what happens in the blood vessels of actual T1D patients during early disease. We will compare the gene expression patterns of cells in our model to data from patients, then use the validated model to test whether blocking specific molecules on blood vessel cells can reduce immune cell infiltration and protect insulin-producing cells from destruction. Our three main goals are: 1) Confirm that blood vessels in the Islet-VMO behave like those in healthy human pancreatic tissue; 2) Confirm the model responds to inflammation the same way T1D patient tissue does; and, 3) Test whether targeting specific blood vessel molecules reduces immune attacks on beta cells. If successful, this work will establish the Islet-VMO as a validated, human-relevant research platform that can accelerate the development of new T1D therapies, reduce reliance on animal models, and align with FDA priorities for more human-relevant preclinical testing.
Anticipated Outcome
Through this project, we anticipate achieving several important scientific and translational outcomes that will meaningfully advance T1D research and accelerate the development of new therapies. Our primary anticipated outcome is establishing the Islet-VMO as a fully validated, human-relevant laboratory model for studying T1D. By demonstrating that our model closely matches real patient tissue, both under normal conditions and during disease-like inflammation, we will create a trusted, standardized research tool that scientists and drug developers worldwide can rely on with confidence. Specifically, we expect the following: 1) to confirm that blood vessel cells in the Islet-VMO closely resemble those in healthy human pancreatic tissue, confirming that our model is a faithful starting point for disease studies; 2) that the model will respond to inflammatory signals, mimicking early T1D, in ways that closely mirror responses observed in real patient tissue, confirming that the Islet-VMO can reliably model the disease state; and, 3) to demonstrate that blocking specific molecules on blood vessel cells can reduce harmful immune cell infiltration and protect insulin-producing cells from destruction. Beyond our immediate scientific results, we expect this project to: provide the T1D research community with a shared, validated platform for studying disease mechanisms and testing therapies; lay the groundwork for official FDA qualification of the Islet-VMO as a recognized New Approach Methodology; and, enable future funding applications and potential commercialization, ensuring the platform reaches the widest possible audience.
Relevance to T1D
One of the greatest challenges in T1D today is that researchers lack reliable, human-relevant laboratory tools to study how the disease begins and progresses. Animal models have contributed enormously to the field, but they cannot fully capture the human immune processes that drive beta cell destruction. As a result, many promising therapies discovered in animals fail when tested in people. The Islet-VMO directly addresses this gap, providing a human cell-based system that models the critical early stages of T1D in a way that has not previously been possible. Qwe hope that the impact of this work will extend beyond our laboratory. Once validated, the Islet-VMO platform can be shared with T1D researchers worldwide, providing a standardized model for studying disease mechanisms and evaluating therapies. This directly aligns with the mission of Breakthrough T1D, which has prioritized validation of advanced human in vitro models as a strategic research goal. These include organ-on-chip systems incorporating stem cell-derived islets, immune cells, and vascular components. In summary, this research tackles a fundamental and persistent unmet need in T1D: a validated, human-relevant model of the early disease process. Its success would meaningfully accelerate progress toward disease-modifying and ultimately curative therapies for the millions of people worldwide living with Type 1 Diabetes.