Objective
The goal of this study is to develop a combinatorial strategy to support and protect transplanted islets by providing local islet-tropic and immune-modulating factors. We aim to enhance graft survival, prevent immune attack of the graft, and promote immune self regulation using bioengineered drug reservoirs to locally release key cell survival factors and regulatory cell therapy. This approach should avoid systemic immunosuppression and long-term dependence on immunosuppression to protect transplanted islets.
Background Rationale
Beta cell replacement therapy restores normal glucose homeostasis by replenishing the lost beta cells through transplantation. However, islet transplant is currently restricted to a few patients with intractable hypoglycemia because of limited islet tissue from deceased donors and the requirement for life-long immunosuppression to prevent graft rejection.
Unfortunately, even the limited donor pancreatic islets are massively lost after transplant due to ischemia. Ischemia can lead to dysfunction of the surviving beta cells and reduction of the efficacy of the therapy. Thus, ischemia injury post-transplant is a major bottleneck for beta cell replacement therapy. Developing mitigating strategies will maximize the limited resources of beta cells regardless of the cell source and potentially reduce the immunogenicity of the transplanted tissue.
Another major hurdle for beta cell replacement therapy is the necessity for immunosuppression that also blunts protective immunity and has undesirable non-immune related toxicities. Beta cells are particularly fragile and sensitive to metabolic and oxidative stress. These characteristics, combined with the lack of ability to regenerate, make islet grafts easier to reject and therefore require stronger immunosuppression to protect. Overcoming this immunological barrier may allow many more patients to benefit from the beta cell replacement therapy.
This proposed study aims to greatly improve the efficacy of islet transplantation and lower the barrier for receiving this therapy by addressing these major hurdles of islet transplantation. We will engineer miniature drug depots that support islet survival in ischemia and modulate immune responses within the islet graft to obviate the need for systemic immunosuppression. If successful, these strategies can be applied to stem-cell derived beta cell transplant to enable wider application of the curative beta cell replacement therapy for type 1 diabetes.
Description of Project
Pancreatic beta cell replacement therapy restores lost beta cell function in patients with long-standing diabetes. With more stem cell derived beta cells entering commercial development and clinical testing, there is an urgent need to overcome other barriers to the wide application of this therapy. Poor engraftment of beta cells in the ischemic post-transplant environment severely limits the efficacy of beta cell replacement by reducing functional beta cell mass. Risks of life-long systemic immunosuppression and its associated morbidity is another significant barrier for the adoption of this therapy.
The two aims of this proposal will address both barriers. Our strategy is to support and protect the transplanted islets with islet-tropic and immune-modulating factors provided by co-implanted polymeric drug depots with the goal of achieving islet mass preservation after transplantation. The aims are based on our expertise in controlled in vivo drug delivery and unique insights in beta cell injury and protection and immune responses to transplanted islets. Successful completion of this study will generate preclinical proof-of-concept data in animal models of islet transplantation.
Anticipated Outcome
The goal of this project is to develop local cell survival and immune modulation strategies to optimize beta cell replacement therapy by improving islet engraftment and prevent immune rejection without the need for systemic treatment. We aim to define the combinatorial composition of agents needed and then engineer delivery strategies to achieve this goal. Successful completion of this study will generate preclinical proof-of-concept data in stringent mouse model of islet transplantation. Future direction includes 1) adaptation of this strategy to human islet and human stem cell derived beta cell transplant in humanized mouse models; 2) combining this strategy with beta cell delivery devices for retrievable transplant; and 3) translational efforts for device manufacturing using clinical application approaches. Ultimately, we envision applying the strategy to clinical islet transplantation or to stem cell derived beta cell therapy to enable immunosuppression-free graft survival.
Relevance to T1D
This study is of direct relevance to type 1 diabetes by developing an approach to support beta cell survival after transplantation and allow for beta cell replacement therapy without the need for long-term systemic immunosuppression.