Objective
Type 1 diabetes (T1D) is a condition in which the body's immune system mistakenly attacks the insulin-producing cells in the pancreas, making it difficult for the body to control blood sugar levels. While current treatments include regular insulin injections or transplantation of insulin-producing cells from deceased donors, these options have significant limitations. One of the biggest challenges is that the immune system can attack and destroy transplanted cells, and most patients must take strong medications to suppress the immune response. These medications can cause serious side effects.
The goal of this research is to develop a new treatment for T1D using pluripotent stem cells that are genetically modified to avoid immune system detection, thus preventing rejection without the need for lifelong immunosuppressive drugs. The research team will use stem cell-derived islet-like clusters (SCILCs) in order to create an abundant source of insulin-producing cells that can be transplanted into patients. The focus of this project is on making these SCILCs "hypoimmune," meaning they can survive and evade the immune system after transplantation.
This research is centered on using an advanced gene-editing techniques (CRISPR/Cas9) to remove a key molecule called ICAM-1 from the SCILCs. ICAM-1 is involved in the immune system's ability to detect and attack transplanted cells (and a patient’s own pancreas in the case of T1D). By deleting this molecule, the researchers aim to stop immune cells from destroying the transplanted SCILCs. This could significantly increase the lifespan of the transplanted cells in T1D patients while avoiding the use of toxic anti-rejection drugs.
The research is broken down into three major objectives (or "Specific Aims"):
1. Understanding Immune Responses in the Lab: The first step is to determine how immune cells from the body react to the ICAM-1 knockout SCILCs in lab experiments. The team will use a range of tools, including advanced immunology assays and RNA sequencing, to study how immune cells from people with and without T1D interact with these genetically edited cells. The goal is to measure how well the gene-edited cells can avoid being attacked by both adaptive immune cells (like T cells) and innate immune cells (like natural killer cells and monocytes).
2. Testing in Humanized Mice: In the second part of the study, researchers will test the gene-edited cells in a special type of mouse model that mimics the human immune system. This will help them evaluate how the ICAM-1 knockout SCILCs perform when transplanted into a living organism with a human-like immune response. The researchers will track how well the cells survive and whether they can successfully produce insulin without being destroyed by the immune system.
3. Addressing Inflammation and Cell Stress: The third aim focuses on how ICAM-1 knockout cells respond to the inflammation and oxidative stress that typically occur during immune attacks. Inflammation can lead to further damage of transplanted cells, so researchers want to see if the gene-editing approach provides additional protection against stress-related cell death. They will measure the ability of the ICAM-1 knockout cells to produce glutathione, which can help protect cells from damage caused by immune-mediated inflammation.
This project is designed to provide new insights into how gene-edited stem cells can be used to create long-lasting, effective therapies for T1D. The potential benefits of this approach are significant: if successful, it could lead to treatments that allow patients to live without the need for daily insulin injections. The ultimate goal is to improve the quality of life for people with T1D by providing a safe and effective stem cell therapy that can be broadly applied to a diverse population of patients.
Background Rationale
Insulin is essential for controlling blood sugar levels, and without it, people with type 1 diabetes (T1D) have to rely on daily insulin injections to survive. Despite this treatment, many patients still struggle to maintain stable blood sugar levels, which can lead to serious complications like heart disease, nerve damage, and kidney failure over time.
One promising way to improve the treatment of T1D is through cell therapy, where insulin-producing cells are transplanted into the patient’s body to replace those that were lost. Deceased donor cells can be used, but this method faces two major challenges: there aren’t enough donor cells to meet the demand, and the patient’s immune system can attack and reject the transplanted cells. This immune rejection can be severe, and patients often need to take strong medications to suppress their immune system. Unfortunately, these drugs can have serious side effects, including infections and cancer.
To overcome these obstacles, scientists are exploring the use of stem cells as an alternative source of cells. Pluripotent stem cells are special because they can be turned into almost any type of cell in the body, including insulin-producing cells known as stem cell-derived islet-like clusters (SCILCs). Preliminary studies and clinical trials with these lab-grown cells show great promise, but the issue of immune rejection remains. One approach to avoid immune rejection is the use of a patient’s own cells to create personalized therapies. This process involves taking a sample of a patient’s cells, reprogramming them into stem cells (called induced pluripotent stem cells), and then turning them into SCILCs. Because these cells come from the patient’s own body, the immune system is less likely to attack them. But in the case of T1D, the patient’s immune system may still destroy these new cells, as it can’t distinguish between the lab-grown cells and the original insulin-producing cells that were mistakenly attacked. Additionally, creating personalized therapies is expensive and difficult to scale for widespread use.
This leads to the rationale for this new Breakthrough T1D research project: creating “off-the-shelf” stem cell therapies that can be used with all patients and that do not trigger an immune response. The idea is to use gene-editing technology to make the transplanted cells “invisible” to the immune system. By editing the genes of SCILCs, researchers can reduce or eliminate the immune system’s ability to recognize and reject the cells. This would provide a solution that could be used for many T1D patients without the need for lifelong immunosuppressive drugs, which can have significant side effects.
The research team uses a cutting-edge gene-editing tool, CRISPR/Cas9, to target a specific molecule called ICAM-1. ICAM-1 plays a crucial role in how immune cells detect and attack cells. By knocking out (removing) the ICAM-1 gene from the insulin-producing cells, the researchers aim to prevent immune cells from binding to and destroying the transplanted SCILCs. This strategy reduces the risk of rejection and makes the therapy more effective and longer-lasting.
The rationale behind this project is that if these gene-edited cells can avoid immune system detection, they could be a paradigm shift for T1D treatment. Patients could receive insulin-producing cell transplants without needing immunosuppressive drugs, greatly reducing the risk of side effects and improving patients’ quality of life. Additionally, this approach has the potential to be used in other conditions related to T1D, such as vascular disease or nerve damage (neuropathy).
By developing immune-protected SCILCs, this research aims to create a breakthrough therapy for T1D that addresses both the shortage of donor cells and the problem of immune rejection, providing a new and potentially curative option for millions of patients worldwide.
Description of Project
Type 1 diabetes (T1D) is a condition where the body’s immune system attacks and destroys insulin-producing cells in the pancreas, making it difficult to regulate blood sugar levels. While transplantation of insulin-producing cells can be an effective treatment, there are two major issues: a shortage of donor tissue, and immune rejection of the transplanted cells.
Scientists are looking for ways to overcome these challenges. One promising approach involves using pluripotent stem cells, which are cells that can be turned into almost any type of cell in the body. Here, the UW-Madison research team is developing insulin-producing stem cell-derived islet-like clusters (SCILCs). These cells can be produced in large numbers in the lab, making it possible to help more patients. Importantly, the research team has developed a new way to protect the SCILCs from the patient’s immune system, which normally attack the cells as foreign invaders. Their approach involves editing the genes of the stem cells to help them evade detection and destruction by the immune system. This process is known as creating “hypoimmune” cells.
The researchers leading this project are working on a new approach to gene editing for T1D treatments. Their goal is to develop a universal donor stem cell line that can be transplanted into any patient, regardless of their genetic background. They are focusing on a specific gene, called ICAM-1, which plays a key role in the immune system’s attack on transplanted cells. By removing or “knocking out” the ICAM-1 gene, they can protect the transplanted cells from being attacked by both the patient’s immune system and the autoimmune response that originally caused T1D.
Previous studies have shown that knocking out ICAM-1 can improve the survival of transplanted cells in other models. Early data from this project suggests that cells without ICAM-1 can still function properly and may be better at avoiding immune system attacks. The researchers will now test their gene-edited cells in lab models that closely mimic human biology, using cutting-edge technology to study how these cells behave in a real immune system.
If successful, this approach could provide a new treatment for T1D that eliminates the need for insulin, as well as avoids lifelong use of immune-suppressing drugs, which can have serious side effects. This new therapy could be made available to a wide range of patients, including those from populations that have historically been underrepresented in medical research.
By developing gene-edited hypoimmune cells, this research could help advance the treatment of T1D and other conditions where the immune system plays a destructive role. The project aims to solve two major problems in T1D therapy: finding a reliable source of insulin-producing cells and preventing their destruction by the immune system. With continued research and clinical trials, this work has the potential to significantly improve the lives of people living with T1D.
Anticipated Outcome
The goal of this research is to develop a groundbreaking new treatment for type 1 diabetes (T1D) by creating insulin-producing cells that can evade the immune system and provide long-term blood sugar regulation. By using advanced gene-editing techniques, the research team aims to modify these cells so they can be transplanted into patients without being attacked by their immune system. The key to this approach is removing a molecule called ICAM-1, which is involved in the immune system’s ability to detect and destroy pancreatic cells. This would make the cells “hypoimmune,” or immune-evasive, potentially eliminating the need for lifelong use of powerful immunosuppressive drugs.
The anticipated outcomes of this research are significant:
1. Creation of a New Class of Gene-Edited Therapies: This research will lead to the development of a new category of therapies that use gene-editing to make transplanted cells invisible to the immune system. This novel approach could be applied to a broad range of conditions, including other autoimmune diseases and transplant rejection, creating new possibilities for immune-tolerant cell therapies.
2. Reduced Dependence on Immunosuppressive Drugs: The need for powerful immunosuppressive medications—which carry serious side effects like infections and cancer—could be eliminated or greatly reduced. Patients receiving these gene-edited insulin-producing cells could enjoy better health, with fewer risks associated with immune suppression.
3. Improved Understanding of Immune Mechanisms: This research will also provide new insights into how adhesion molecules like ICAM-1 contribute to immune rejection and T1D autoimmunity. By studying how the immune system responds to gene-edited cells, researchers will deepen their understanding of the underlying mechanisms of allorejection (the body’s rejection of transplanted tissues) and autoimmune disease, opening up new avenues for future research.
4. Long-Lasting Cell Function and Broader Applications: The gene-edited cells are expected to function long-term in the body, producing insulin and maintaining healthy blood sugar levels. This would reduce or eliminate the need for daily insulin injections, offering a more stable and effective solution for T1D patients. Additionally, this approach could pave the way for similar treatments for other conditions, such as vascular disease and nerve damage, which can affect the health and quality of life of people with T1D.
In summary, this research not only holds the promise of a safer and more effective treatment for T1D, but also represents a new direction for gene-edited therapies. By creating immune-tolerant cells and improving our understanding of how the immune system interacts with these cells, this work could have far-reaching impacts on the treatment of many immune-related conditions.
Relevance to T1D
Type 1 diabetes (T1D) is a lifelong condition in which the body’s immune system attacks and destroys the insulin-producing cells in the pancreas. Without insulin, blood sugar levels cannot be controlled, so people with T1D must carefully manage their blood sugar through daily insulin injections or an insulin pump. Even with the best management, blood sugar levels can fluctuate, making it difficult to maintain stable control. Over time, these fluctuations can lead to serious complications, such as heart disease, kidney failure, vision loss, nerve damage, and poor circulation. Living with T1D is a constant challenge. Patients must monitor their blood sugar multiple times a day, count carbohydrates with every meal, and adjust their insulin doses accordingly. The constant need for vigilance can affect every aspect of life, including work, school, and social activities. The complications of T1D, even when managed, are a significant burden for patients and can reduce their quality of life.
This research project is directly aimed at changing that reality. By developing a new kind of cell therapy that could replace the lost insulin-producing cells, this project has the potential to provide a breakthrough treatment for people with T1D. Using advanced gene-editing technology, University of Wisconsin-Madison researchers are working to create insulin-producing cells from pluripotent stem cells, which are cells that can be turned into almost any type of cell in the body. This cell therapy, known as stem cell-derived islet-like clusters (SCILCs), can be transplanted into patients to take over the role of producing insulin, potentially eliminating the need for daily injections.
What makes this research especially relevant to T1D is its focus on making these cells immune-evasive, meaning they can be transplanted without being attacked by the multiple aspects of the immune system that contribute to T1D as well as loss of transplanted cells. Current transplantation approaches face significant challenges because the immune system often rejects the transplanted cells, requiring patients to take powerful drugs that suppress their immune system. These drugs can have serious side effects, including increasing the risk of infections and cancer. The new approach in this research removes a key molecule, ICAM-1, which plays a role in immune system detection. By knocking out this molecule in the transplanted cells, the researchers hope to create cells that the immune system can’t recognize and attack, allowing for long-lasting cell function without the need for immune suppression.
The success of this project would mark a significant advance in T1D treatment. It could allow patients to live without the constant burden of managing their blood sugar levels, improve their quality of life, and reduce the risk of complications caused by the disease. For patients who have struggled with the limitations of insulin therapy, this approach offers a glimpse of a future where they might no longer need daily injections or pumps.
In addition to treating T1D, this research platform could be expanded in the future to address other serious complications that affect people with the disease. For example, the same gene-editing techniques could be used to develop treatments for vascular disease, nerve damage (neuropathy), or kidney problems, which are all too common in T1D. By building on this hypoimmune platform, the research could lead to a range of cell-based therapies that target the major complications of T1D and improve patients' health in multiple ways.
This research has the potential to change the landscape of T1D treatment, offering a new and promising solution for both managing the disease and addressing its long-term complications.