Objective
The objective of this project is to develop and test a new material called “ToleroGel” that can protect transplanted insulin-producing “beta” cells from immune attack without requiring lifelong immunosuppressive drugs that can have adverse side effects.
Specifically,
1. We will determine the ToleroGel formula that ensures the survival of transplanted cells during and after the injection process and their function (effective production of insulin in response to glucose exposure). We will test these goals using several types of insulin-producing cells, progressing from basic mouse cell lines to cells derived from human stem cells.
2. We will test whether ToleroGel can protect transplanted cells in mice that naturally develop autoimmune diabetes (similar to human T1D). This model will test whether our approach can prevent the same type of adverse immune attack that originally destroyed the patient's own beta cells.
3. We will determine whether ToleroGel can protect transplanted cells that come from a genetically different donor. Since stem cell-derived replacement cells will not be genetically matched to patients, the immune system will try to reject them as “foreign.” This second mouse model will test the robustness of our approach against this type of immune rejection.
By the end of this three-year project, we will know whether and how ToleroGel will protect transplanted insulin-producing cells and restore normal blood sugar control by overcoming two challenges that cell replacement therapy must overcome: (a) the autoimmune attack specific to T1D and (b) the rejection of donor beta cells.
Background Rationale
Type 1 diabetes occurs due to a defect in the immune system’s ability to maintain tolerance toward the insulin-producing beta cells in the pancreas. As the immune system destroys the insulin-producing beta cells in the pancreas, the body’s normal ability to regulate the blood sugar level is severely affected. As a result, affected patients must take insulin injections for life. Despite advances in insulin delivery and blood sugar monitoring, many people with T1D still experience dangerous swings in blood sugar that can lead to seizures, loss of consciousness, and other adverse symptoms.
Replacing the destroyed beta cells with new, healthy ones offers the possibility of restoring the body's natural blood sugar regulation. Recent clinical trials (for example, a trial conducted by Vertex) have shown that beta cells grown from stem cells can successfully produce insulin and eliminate dangerous low blood sugar events in patients. The problem is that these transplanted cells are recognized as foreign by the recipient’s immune system, which tries to attack and destroy them.
Currently, the only way to protect transplanted cells is through drugs that suppress the activity of the entire immune system. While effective at preventing rejection, these drugs increase the risk of infections and cancer, require lifelong use, and carry other side effects. Because of these risks, cell replacement therapy can only be used in patients whose T1D is so severe that the risks of immunosuppression are justified.
Our approach takes a fundamentally different strategy: instead of suppressing the entire immune system, we aim to teach it to specifically accept the transplanted cells. We do this using a natural protein signal called an immune checkpoint that the body already uses to tell the immune system not to attack certain tissues. For example, during pregnancy, this protein helps prevent the mother's immune system from attacking the developing fetus.
We have attached this protein to an injectable gel material that can carry transplanted cells to various sites in the body. When immune cells encounter the transplanted cells in the presence of this B7x signal, they are reprogrammed from attackers into protectors called “regulatory T cells.” These regulatory cells then provide long-lasting protection (also called “induced self-tolerance”) for the transplant.
This local approach preserves the immune system's ability to fight infections and cancer throughout the rest of the body, thus meeting a key requirement for any tolerance strategy to be clinically viable.
Description of Project
In people with type 1 diabetes (T1D), immune cells of the body destroy the insulin-producing cells (called beta cells) in their pancreas, disrupting normal blood sugar control. Although insulin injections are used to manage the symptoms, individuals remain vulnerable to hypoglycemic (very low blood sugar level) episodes and long-term complications affecting the eyes, kidneys, and heart.
Replacing the destroyed cells with new insulin-producing cells offers the promise of a cure, restoring the body's ability to automatically regulate blood sugar. Recent clinical trials using cells grown from stem cells have shown remarkable results: most patients achieved normal blood sugar levels without needing insulin injections one year after such cell therapy. However, there is a significant limitation. Because these replacement cells come from a donor, the recipient's immune system recognizes them as foreign and tries to destroy them, using a similar mechanism involved in the rejection of a transplanted organ.
Currently, the transplanted cells are protected using immunosuppressive drugs that patients for the long term. Such immunosuppression disrupts the body’s normal immune defense against external (e.g., bacteria and viruses) and internal (e.g., developing tumors) threats. Hence, long-term use of these drugs increases a patient’s susceptibility to infections and cancer. For most people with T1D—especially and young patients—these risks outweigh the benefits of cell replacement therapy.
Our proposed project aims to solve this problem by developing a new approach that teaches the immune system to accept transplanted beta cells without the need for lifelong immunosuppression. We have created “ToleroGel,” an injectable gel material that carries a natural immune-calming protein signal. When transplanted cells are delivered within ToleroGel, the protein signal instructs local immune cells to become “regulatory” cells that protect the transplant rather than attack it.
A key advantage is that this re-education of the immune system happens locally at the site of injection. Rather than suppressing the entire immune system throughout the body (which would leave patients vulnerable to infections everywhere), ToleroGel creates a protected zone specifically around the transplant site. The rest of the immune system remains fully functional to fight infections and cancer.
Our preliminary experiments show that ToleroGel successfully creates these protective immune cells in mice and retains the protein signal at the injection site for over a month. We have also shown that the protective effects remain in other models of inflammatory disease.
In this project, we will test whether ToleroGel can protect transplanted insulin-producing cells in two different mouse models of diabetes. The first model mimics the autoimmune attack seen in T1D. The latter tests whether ToleroGel can prevent rejection of cells from a different genetic background — this is important because stem cell-derived cells will come from donors. We will track blood sugar levels, measure insulin production, and examine the immune cells at the transplant site to understand how ToleroGel provides protection.
If successful, this research will transform cell replacement therapy from a treatment reserved for only the most severe cases of T1D into an option available to millions of people living with the disease. By eliminating the need for immunosuppressive drugs, we could make this potentially curative therapy accessible to children and young adults.
Anticipated Outcome
We anticipate the following outcomes from this project:
Year 1: We expect to identify the ToleroGel formula that keeps transplanted cells alive and functional, during and after injection. We will determine the specific types of materials that i) result in the delivery of live cells (exceeding cells in solution alone which experience large forces during injection) and ii) also promote the function of insulin-producing beta cells through physical signals. We anticipate that cells encapsulated in ToleroGel will survive the injection process with greater than 80% viability and maintain or potentially improve their ability to produce insulin in response to sugar.
Year 2: We expect to demonstrate that ToleroGel can protect transplanted cells in mice with autoimmune diabetes. Based on our preliminary data showing strong production of regulatory T cell (immune cells that protect the body and signal tissue repair), we anticipate that cells delivered in ToleroGel-protected transplants will survive significantly longer than unprotected transplants. We expect to see increased levels of regulatory T cells and decreased levels of inflammatory immune cells at the transplant site.
Year 3: We expect to confirm that ToleroGel also protects against rejection of donor cells and to assess how long the protection lasts. We will test whether the protective immune cells persist even after the gel material has degraded—if so, this would suggest that ToleroGel induces true long-term “tolerance” rather than temporary immune suppression.
If successful, this project will provide strong evidence that ToleroGel can enable cell replacement therapy without lifelong need to suppress the immune system in patients. This would lay the groundwork for: (a) advanced studies in larger animals (e.g., non-human primates) to confirm safety and efficacy, (b) manufacturing development to produce ToleroGel at clinical scale, and (c) regulatory discussions with the FDA about phase I/II clinical trials.
The potential impact of the proposed project is substantial. If ToleroGel can eliminate the need for immunosuppressive drugs, cell replacement therapy could become available to the millions of people with T1D who currently cannot access it due to risks associated with indiscriminate immunosuppression. This includes children and young adults who would otherwise face decades of living with diabetes and its debilitating complications.
Relevance to T1D
This project directly addresses one of the most significant barriers to curing (in contrast to managing) type 1 diabetes: the need for lifelong suppression of the immune response after cell replacement therapy to achieve insulin independence.
Why cell replacement matters for T1D: Type 1 diabetes is fundamentally a disease that occurs due to the loss of insulin-producing beta cell. The immune system destroys these insulin-producing cells in the pancreas, and they do not regenerate. Unlike type 2 diabetes, which can often be managed with lifestyle changes and oral medications, T1D requires lifelong insulin replacement for survival. Cell replacement is the only approach that can restore the body's natural ability to produce and regulate insulin. In particular, manufacturing of human stem cell-derived islets have proven to be scalable, and such products are poised to become a crucial curative therapeutic strategy.
The limitation of long-term immunosuppression: Recent clinical trials have proven that stem cell-derived beta cells can cure diabetes in humans—patients have achieved normal blood sugar levels without insulin injections. However, these remarkable results require immunosuppressive drugs that increase risks of infection and cancer. For the T1D community, which includes many children and young adults facing 50+ years of disease, these risks are unacceptable for many patients.
How the proposed project addresses this challenge: ToleroGel represents a fundamentally new approach to protecting transplanted cells. Rather than suppressing the entire immune system with drugs, ToleroGel works locally at the transplant site to convert attacking immune cells into protective ones. This targeted approach will preserve the body's ability to fight infections and cancer, meeting an urgent need for the T1D community.
Alignment with priorities of Breakthrough T1D: This project directly addresses the RFA's goal of tolerance induction toward “islet cell therapy that enables graft-specific immune protection without compromising natural immune defenses.” Our approach is specifically designed to be compatible with scalable stem cell-derived islets, positioning it for integration with the next generation of cell therapies already in clinical development. Furthermore, our proposed project will address two key immune challenges associated with T1D: allorejection (driven by the recognition of “foreign” cells) and autoimmune recurrence (driven by the reactivation of pre-existing immune cells specific for the islets of the patient).
Potential impact for people with T1D: If successful, this research will transform cell replacement from a last-resort treatment into a widely available option for people with T1D. Instead of choosing between risky immunosuppression or indefinite insulin dependence, patients will receive cell therapy that their bodies accept. The resulting preservation of functional beta cells will mean freedom from insulin injections, elimination of dangerous low blood sugar episodes, and prevention of long-term complications of diabetes.
For families affected by T1D, this research represents a hope for a true cure, rather than better disease management. Restoration of the body's natural ability to safely regulate blood sugar will improve the quality of life for millions of patients with T1D.