SA-FasL-engineered human islets as a novel product for the treatment of type 1 diabetes

Fascure Therapeutics, Llc, Louisville KY

Investigators

Abstract

PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However, immune rejection and continuous use of immunosuppression to control rejection are two major limitations of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. FasCure Therapeutics is focused on the development of biologics with desired immune modulatory activities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immune inhibitory ligands as components of an immunomodulatory platform for prevention and treatment of autoimmune diseases and graft rejection. The Company?s lead therapeutic platform includes islets engineered with a novel form of Fas ligand immunomodulatory protein, SA-FasL. T cells are the main culprits of T1D as well as allogeneic islet graft rejection. T cells upregulate Fas receptor on their surface following antigen activation, and become sensitive to Fas/FasL-mediated apoptosis. Importantly, FasL-induced apoptosis plays an important role in T cell homeostasis and tolerance to self-antigens. As such, SA-FasL has significant potential for the induction of tolerance to auto and alloantigens. Consistent with this notion, the transient display of SA-FasL protein on pancreatic islets have shown robust efficacy in overcoming immune rejection in various allogeneic and xenogeneic rodent transplantation models. The major goals of this phase I STTR application is to: i) assesses the feasibility of engineering human islets with SA-FasL protein without negatively impacting their function, and ii) test the efficacy of SA-FasL-engineered islets in overcoming rejection in a humanized mouse model in the absence of continuous immunosuppression. If feasibility and efficacy are shown in the humanized mouse model, the SA-FasL-engineered human islets will be further developed as a novel product in a Phase II STRR application for translation into clinic.