Objective
Our objective is to advance beta cell replacement therapies for type 1 diabetes by evaluating novel strategies that mitigate immune-mediated destruction and enhance the survival of transplanted beta cells. Here, we aim to achieve this through two primary approaches:
First, the approach we propose here has as its backbone the use of a class of drugs called JAK inhibitors. JAK inhibitors are well-tolerated drugs with minimal adverse risks compared to conventional immunosuppressants. Despite this, they remarkably have not been used extensively in transplantation although they have resulted in promising trial data. By testing these inhibitors in preclinical models of beta cell transplantation, we seek to determine their efficacy in promoting long-term graft survival without the need for other immunosuppressive drugs. This approach aims to reduce the risk of rejection, infections, and other adverse effects associated with current immunosuppressive treatments, while preserving overall immune function and graft survival.
Second, we will explore genetic modification strategies using CRISPR/Cas9 technology to engineer islets and stem cell-derived beta cells that will not trigger an immune response. This will be accomplished by either deleting genes involved in immune recognition, or overexpressing genes that protect from immune detection. The objective here is to make beta cells less visible and susceptible to immune attack, improving their survival and functionality post-transplantation. We will also elucidate the mechanisms underlying allogeneic immune response dynamics and beta cell survival in T1D to inform on future studies designed to enhance graft outcomes in patients.
By systematically assessing the efficacy of these approaches, we seek to establish robust protective mechanisms that can sustain the long-term function and protection of transplanted beta cells without chronic immunosuppression.
Background Rationale
Current strategies for beta cell replacement include islet transplantation, where insulin-producing cells from donor pancreases or stem cell-derived products are infused into patients. However, this approach is severely limited by a lack of supply of suitable donor organs and the need for chronic immunosuppression to prevent graft rejection. Current immunosuppression protocols are not ideal as they do not adequately address the early loss of islets in the period immediately following transplantation. Because of this, grafts can be rejected, and there is an inherent risk for toxicity for both the transplanted islets and the recipient, including ongoing side-effects from immunosuppression, including infection and/or malignancy.
To overcome this, establishing durable immune tolerance of the graft while maximizing the function of transplanted beta cells is preferable to long-term drug treatment to maintain graft survival. This will most likely require a combinatory approach of inactivation of immune cells at the graft site and/or masking of the grafted islets from the immune system, together with a well-tolerated immunomodulatory drug for maintenance.
JAK inhibitors are a class of drugs that are well-tolerated with minimal adverse risk that we can use to achieve this. JAK inhibitors can prevent immune activation and reduce inflammation at the site of the graft, lessening the risk for an immune response against transplanted islets. Our recent clinical trial suggests they are effective in protecting against beta cell loss in recently diagnosed patients with T1D. Encouraged by these findings, we are poised to apply this strategy in tandem with genetic editing of grafted islets to maximize their protection and functionality. The advent of CRISPR editing has allowed us to engineer powerful new tools and platforms to manipulate beta cells and make them less recognizable and vulnerable to immune attack.
Given that immune attack of beta cells involves both T cells and the beta cells themselves, it may be advantageous to simultaneously target both by making the beta cells less visible to the immune system, and the T cells less prone to activation and attack. We propose that combination of JAK inhibition and genetic editing of islets can help us achieve this goal and maintain long-term tolerance towards the graft.
Description of Project
Type 1 diabetes (T1D) results from the immune system, particularly T cells, destroying insulin producing beta cells in the pancreas. This leads to insulin deficiency, necessitating lifelong insulin injection therapy for patients to maintain their blood sugar levels. However, while insulin injections are effective in controlling blood sugar, they do not cure T1D. They may also put patients at risk for complications and under the financial and medical burden of continuous management. Therefore, it is important to identify strategies geared towards a long-lasting cure, not just ways to treat the condition. Our goal is to introduce preventative and curative strategies for T1D into clinical practice that are based on scientific understanding of disease mechanisms and that will challenge insulin as the main treatment. This entails addressing the underlying immune-mediated destruction of beta cells, and exploring alternative strategies to potentially replace insulin therapy altogether.
For individuals with established T1D who have little residual insulin production, beta-cell replacement is a necessary component of a cure strategy. Currently, islet transplantation offers a viable treatment option, but it is severely limited by the scarcity of donor organs, the requirement for systemic immunosuppression to prevent graft rejection, and the risk of autoimmune recurrence if systemic immunosuppression is reduced. Stem cell-derived beta cells have generated considerable promise, but they remain vulnerable to immune attack and would likely still require systemic immunosuppression.
This project has two aims. First, to determine the effect of a class of drugs called JAK inhibitors on islet graft survival in a mouse model of T1D. This aim will entail testing JAK inhibitors alone, or in synergy with genetic editing of islets to mask them from immune detection. We will perform comprehensive molecular analyses to understand how graft rejection differs from beta cell autoimmunity, and determine how JAK inhibition and/or islet editing impacts the T cells and grafted beta cells. Second, we will use human pluripotent stem cell derived beta cells and T cells to model and study interactions between a graft and the recipient’s immune system. This is critical in helping further our understanding of how the immune system sees and responds to a foreign graft, and we can apply what we learn to develop new targeting strategies.
Our proposed approach has several important advantages. First, JAK inhibitors are widely used and well-tolerated immunomodulatory drugs with fewer risks and a better safety profile compared to conventional immunosuppressants, as shown by our recent clinical trial investigating JAK inhibitor baricitinib in newly diagnosed patients with T1D. Second, as opposed to being limited by donor organ availability, stem cells offer a potentially limitless source of beta cells for transplantation. This is compounded by the advent of CRISPR technology that has enabled the development of tools to feasibly and reliably edit stem cells for our studies. To accomplish this, we will be working with internationally recognized experts in stem cell differentiation and development, Prof. Ed Stanley and Dr. Jacqui Schiesser.
If our studies are successful, we can use our pre-clinical data to approach pharma to support testing the approach in clinical islet transplantation and translate these findings into real life applications. Leveraging our team’s successful islet transplantation program in Australia, we are well positioned to validate and test these innovative approaches in beta cell replacement therapy.
Anticipated Outcome
The anticipated outcomes of our research hold promise for transforming the landscape of canonical T1D treatment by addressing key challenges and advancing towards potential cures. Upon completion of this project, we will:
1. Have determined whether JAK inhibitors can protect islets after transplantation, and if they can be combined with genetic modification of grafted beta cells to reduce local inflammation, limit graft rejection, and maximize graft function. If successful, this approach could mitigate the risks associated with current treatments, such as infections and organ toxicity, fulfilling an unmet need of a safer and more sustainable alternative for individuals with T1D.
2. Have defined the feasibility for using genetically edited stem cell-derived beta cells as a renewable source of beta cells for transplantation. We expect to enhance the resilience of beta cells against immune attack by making them less recognizable by the immune system. In doing so, we aim to advance the development of non-immunogenic stem cell-derived beta cells that are robust and functionally equivalent to natural beta cells.
3. Have addressed a gap in knowledge by unraveling the mechanisms underlying allogeneic immune responses in comparison to beta cell autoimmunity in T1D. Through our comprehensive analyses, we will define how JAK inhibitors and genetic modifications influence the immune system and grafted islets in these processes. These insights will identify new targeting modalities and provide a foundation for designing better and targeted therapies that can be used in the clinic.
If our studies are successful, we can use our pre-clinical data to approach pharma to test these strategies in clinical islet transplantation. Given our team’s established islet transplantation program in Australia, we are well positioned to refine and test these innovative approaches in beta cell replacement therapy.
Relevance to T1D
Our proposed research is extremely relevant to T1D in addressing critical challenges and exploring innovative approaches towards better treatments and potential cures. Current insulin therapies, while life-saving, have limitations, because they do not cure T1D and require precise management to avoid complications. Moreover, the reliance on insulin injections can be burdensome due to financial, logistical, and medical challenges. Therefore, there is a crucial need for new treatment strategies that can offer long-term solutions and improve the quality of life for individuals with T1D.
Our research focuses on unifying two promising avenues: JAK inhibitors and genetic editing of beta cells, particularly stem cell-derived beta cells, which have shown potential as a renewable source of insulin-producing cells. But even with a bank of stem cells to generate beta cells, they will still have some degree of mismatch with the transplant recipient, which may actually increase autoimmune attack. To overcome this, we are taking advantage of advances made in CRISPR editing to cloak them from immune detection, and synergizing this approach with JAK inhibitors, a class of drugs that modulate the immune system in a more targeted and safer manner compared to traditional immunosuppressants.
By approaching this critical problem from multiple angles, we endeavor to overcome the limitations of current therapies by providing a more sustainable and effective treatment option for T1D. Ultimately, our work seeks to translate scientific discoveries into clinical applications. If successful, our findings could lead to new treatments that reduce or eliminate the need for insulin injections, improving patient outcomes and offering hope for a future where T1D is effectively cured.