An immunomodulatory and vascularized cell delivery device for type 1 diabetes cell therapy

PROJECT SUMMARY An immunomodulatory and vascularized cell delivery device for type 1 diabetes cell therapy The overall goal of this proposal is to develop a cell-retaining, subcutaneous device that allows blood vessel penetration and establishment of an immunotolerant environment for islet delivery for type 1 diabetes cell replacement therapy. Transplantation of human cadaveric islets and more recently human stem cell-derived insulin-producing cells has shown great promise as a curative therapy for T1D patients. However, delivering the cells safely and maintaining their long-term function without immunosuppression remains a daunting challenge. In principle, encapsulating the cells in a semi-permeable biomaterial or device can protect the cells from the immune system but the approach introduces a physical barrier and prevents direct vascularization, diminishing the mass transfer and cellular function over time. On the other hand, the “open” approach aims to support cell engraftment by establishing an immunotolerant local environment and allowing host integration and vascularization. We recently developed a cell-mediated “open” approach where we co-transplanted genetically engineered “nurse” cells (engineered mesenchymal stromal cells over-expressing PD-L1/CTLA-4Ig, or eMSCs) together with islets to induce local immunotolerance for immunosuppression-free allogeneic islet engraftment in mouse kidney capsules. However, a caveat in our approach that limits its long-term efficacy is that the eMSCs, similar to numerous MSC products that are currently evaluated in clinical trials, are migratory and they do not stay co-localized with islets. To overcome this cell retention problem, we engineered an electrospun nonwoven cell delivery device that retained the MSC cells while allowing capillary penetration in subcutaneous space of mice. The objective of this project is to test the hypothesis that improving the retention of eMSCs and their co- localization with islets in this cell-retaining, vascularized “open” device will enhance the immunomodulatory effects and prolong the therapeutic efficacy of allogeneic islet transplantation in a clinically attractive subcutaneous site. Successful completion of this project will result in the development of an immunomodulatory device that can be subcutaneously implanted, enabling both capillary penetration and establishment of an immunotolerant environment for islet engraftment without requiring chronic systemic immunosuppression.