Raphael ThysUnlocking the potential of renewable β cells and precision gene editing, researchers aim to revolutionize diabetes care and bring us closer to a functional cure for type 1 diabetes.
Review Article: . Image Credit: Andrii Yalanskyi / Shutterstock
In a recent study published in the journal Nature Reviews Endocrinology, researchers examined the progress in cell replacement therapies for type 1 diabetes mellitus (T1DM), focusing on generating replenishable β cells, improving transplantation methods, and addressing challenges related to immune modulation and clinical application.
Background
T1DM affects 8.75 million people globally, approximately 1.52 million patients under 20. T1DM results from the autoimmune destruction of pancreatic β cells, consequent insulin insufficiency, and chronic hyperglycemia. Although glucose monitoring and insulin dosing help manage the disease, achieving optimal glycemic control remains challenging. Pancreatic islet or β cell transplantation offers a potential cure but faces challenges such as limited donor availability, poor cell engraftment, and the need for lifelong immunosuppression. Current research focuses on improving cell delivery, finding alternative cell sources, and reducing reliance on immunosuppression. In the present review, researchers discussed the current advancements in cell transplantation for T1DM, focusing on β cell generation, delivery technologies, immune modulation, relevant animal models, and the clinical translation of these therapies.
Renewable islet cell sources
The limited availability of donor islets has driven the development of stem cell-derived islets as a renewable source for T1DM therapy. These islets, generated from human pluripotent stem cells (hPSCs), show promise in clinical trials but remain challenged by functional immaturity, transcriptional identity issues, and the inability to control the ratio of β, α, and δ cells. During in vitro differentiation, a significant number of cells may acquire an unwanted identity, resembling serotonin-producing enterochromaffin cells, which complicates their application in T1DM therapy. While in vivo transplantation can enhance the function of these cells, optimizing in vitro production processes and ensuring safety, particularly concerning uncommitted cell types that could form tumors and ensuring genetic stability, remains crucial. Advances in scalable manufacturing, characterization protocols, and cryopreservation will be essential for the clinical adoption and accessibility of these therapies.
Cell delivery strategies
Pancreatic islet transplantation for T1DM involves strategies like microencapsulation and macroencapsulation to protect islet cells and enhance their function. Microencapsulation encloses cells in gel-like microspheres, allowing nutrient exchange while shielding them from immune attacks. However, challenges like inflammation and fibrotic overgrowth affect long-term viability. Macroencapsulation delivers larger cell doses in retrievable units but faces issues with oxygen supply and fibrosis. Open devices and scaffolds aim for direct vascularization of grafts to improve integration and function, using approaches like simultaneous implant-transplant methods, decellularized tissue scaffolds, and 3D-printed architectures. Prevascularization systems are also explored to establish a vascular network before cell transplantation, improving cell survival and reducing immune responses. Despite these innovations, ensuring adequate mass transfer of oxygen, glucose, and insulin within encapsulation devices and managing graft size and immune protection remain significant hurdles. While these approaches show promise, challenges remain in achieving long-term efficacy, minimizing immune rejection, and optimizing oxygen and nutrient delivery to transplanted cells.
Alternative immunoprotection methods
β cell replacement faces challenges distinct from non-autoimmune diseases, mainly due to the need to prevent autoimmunity recurrence. Current immunosuppressive therapies are effective but have severe side effects, including organ toxicity and increased infection risks. Emerging strategies focus on more targeted, less toxic immunomodulation. These include biomaterial-based localized drug delivery, islet co-delivery with immunomodulatory cells, and reducing islet graft immunogenicity through advanced gene editing techniques. Biomaterials can deliver immunomodulatory drugs directly to the transplant site, while co-delivery with cells like mesenchymal stem cells improves islet survival. Gene editing technologies, such as CRISPR–Cas9, are being utilized to engineer hypoimmune islet grafts by knocking down immunogenic markers or overexpressing protective signals. However, the long-term impact of these genetic modifications remains uncertain, and safety concerns persist regarding the potential for immune evasion by these modified cells.
Animal models
Animal models support the development of cell transplantation strategies and immunomodulatory interventions. Immunocompromised models, mainly using mice, allow for studying human islet engraftment without rejection. In contrast, immunocompetent models, such as rats, pigs, and non-human primates (NHPs), better mimic human immune responses critical for evaluating inflammatory and immune protection strategies. Humanized models, incorporating human immune components, provide a unique platform to assess the immunogenicity of β cell grafts and therapeutic interventions despite limitations such as graft-versus-host disease and shorter experimental timeframes. Pigs provide insights into islet transplantation due to their physiological similarities to humans, while NHPs serve as valuable translational models, contributing to understanding immune responses and developing new immunosuppressive strategies. Together, these models facilitate comprehensive assessments of therapeutic interventions for T1DM.
Clinical translation
Harmonizing preclinical testing protocols is vital for β cell replacement therapy development. Characterization of stem cell-derived β cells should include composition and functional assessments. Initial rodent studies must evaluate cell delivery and immune responses, with further validation in larger animal models. Development of a β cell replacement product involves renewable cell sources, effective delivery, and immune rejection prevention. The goal is to create a safe, reproducible product that restores glycemic control for over ten years without systemic immunosuppression.
Conclusion and outlook
In conclusion, cell transplantation for T1DM has evolved significantly, with stem cell-derived islets showing promise for clinical application. However, challenges related to cell composition, functional maturity, and long-term safety continue to be critical areas of focus. Collaborative consortia are accelerating progress by integrating complementary technologies. Innovations in renewable β cell sources, gene editing technology, and subcutaneous transplantation methods aim to improve cell delivery, immune modulation, and patient outcomes. The goal is to develop a widely applicable, practical, and accessible treatment that improves the quality of life for T1DM patients.
Journal reference:
- Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead. Grattoni, A. et al., Nature Reviews Endocrinology (2024), DOI: 10.1038/s41574-024-01029-0, https://www.nature.com/articles/s41574-024-01029-0