Exploiting activation-induced cell death as a means of inducing tolerance to kidney allografts

PROJECT SUMMARY Kidney transplantation is the preferred treatment for patients with end stage renal diseaseHoweverstandard immunosuppression to control rejection is the major limitationAlthough standard immunosuppression has gradually been improved for better efficacy and safetyit still carries a great risk for adverse effects ranging from malignancies and infections to cardiovascular complicationsAs suchthere is an acute need for developing novel immunomodulatory approaches that obviate the need for chronic immunosuppression or mitigate immunosuppression for improved safetyThe goal of this phase I SBIR application is to simultaneously target Fas and ILR as an innovative immunomodulatory approach to modulate pathogenic T effectorTeffand protective T regulatoryTregcells for induction of tolerance to rat kidney allografts in the absence of any immunosuppressionFasCure Therapeutics is focused on the development of biologics with desired immunomodulatory activities for targeted indicationsThe Company has exclusive rights to a portfolio of proprietary novel immune inhibitory ligands as components of a therapeutic platform for prevention and treatment of autoimmune diseases and foreign graft rejectionThe Company s lead therapeutic platform involves the use of SA FasL and ILD as novel forms of Fas and ILR agonistsrespectivelyto directly target pathogenic Teff cells for physical eliminationapoptosisand protective Treg cells for expansionTeff cells are the main culprits of allogeneic graft rejectionThese cells upregulate Fas receptor on their surface following antigen activationand become sensitive to Fas FasL mediated apoptosisILis critical for the generation and expansion of CDCDFoxPTreg cellsILis also involved in apoptosis of Teff cells by down regulating anti apoptotic genesAs suchthe combination of SA FasL and ILD has the potential to physically eliminate Teff and expand Treg cellsAn increased Treg Teff ratio has significant potential to sustain renal allograft survival in the absence of chronic immunosuppressionThis notion is supported by strong preliminary data in allogeneic pancreatic islet and cardiac graft models in miceThe major goals of this phase I SBIR application is toiestablish a lead SA FasL ILD treatment protocol that sustains permanent rat kidney allograft survival in the absence of any immunosuppressionand iiinvestigate the mechanistic basis of sustained graft survival and the safety profile of the immunomodulatory protocolIf efficacy is shown in the proposed rat modelthis protocol will be further developed as a novel product in a Phase II SBIR application for translation into nonhuman primates as a prelude to clinical trials PROJECT NARRATIVE Kidney transplantation is the preferred treatment for patients with end stage renal diseaseHoweverstandard immunosuppression to control rejection is the major limitation as it carries a great risk for adverse effects ranging from malignanciesinfectionsand cardiovascular complicationsAs suchthere is an acute need for developing novel immunomodulatory approaches that obviate the need for chronic immunosuppression or mitigate immunosuppression with improved safetyThe goal of this phase I SBIR application is to use two novel biologics as an innovative immunomodulatory approach to achieve permanent renal allograft survival the absence of chronic immunosuppression as a prelude to clinical trials