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