Therapeutic Adjunct to Improve Immunosuppression Outcomes Following Organ Transplantation

AbstractTherapeutic Adjunct to Improve Immunosuppression Outcomes Following Organ Transplantation The goal of this project is to develop a safemicrobiome targeted therapeutic to improve outcomes associated with mycophenolateMPAan immunosuppressant commonly prescribed for acute and long term prevention of organ rejection after transplantation surgeryThe therapeutic potential of MPA is frequently compromised by intolerable diarrhea that results in MPA dose modification inof recipients in the firstmonths of therapyMPA is the active moiety in two approvedwidely used immunosuppressant drugsmycophenolate mofetil and sodium mycophenolateMPA blocks B and T cell activation by inhibiting inosinemonophosphate dehydrogenasean enzyme that is also important for growth and replication of enterocytesMPA is detoxified by liver enzymes to the inactive phenolic MPA glucuronideMPAGMPAG is excreted in bile and delivered to the intestinal lumenwhere bacterialglucuronidasesGUSin the intestinal microbiota cleave MPAG back into its active MPA moietyMPA produced in intestinal lumen is thought to exert several toxic effects to adjacent enterocytesWe hypothesize that MPA induced diarrhea can be ameliorated by inhibiting the activity of bacterial GUS to reduce luminal production of toxic MPAThis proposal aims to validate this therapeutic hypothesis based on ex vivo and in vivo studies that collectively demonstrateEx vivo protein preparations isolated from rat intestine effectively cleaves MPAG to MPAand this cleavage can be reduced by novel and selective GUS inhibitorsDiarrhea induced by MPA in rats can be alleviated with a proprietary bacterial GUS targeted inhibitorandPharmacologic inhibition of bacterial GUS can ameliorate MPA induced diarrhea without significantly reducing systemic exposure of MPAThe proposed studies provide proof of concept that the microbiome can be selectively targeted to improve outcomes associated with MPA therapyThis Phaseproject provides the groundwork for lead optimization and preclinical development activities in PhaseProject NarrativeTherapeutic Adjunct to Improve Immunosuppression Outcomes Following Organ Transplantation Immunosuppressant drugs have dramatically increased the lifespan of organ transplantation recipients by reducing the risks associated with organ rejectionHowevertheir therapeutic benefit is compromised because of intolerable druginduced toxicitiesFor exampleof patients need to reduce or stop dosage of the widely prescribed immunosuppressant mycophenolateMPAdue to MPA induced diarrheawhich increases the risk of graph rejection and deathThis proposal aims to evaluate several proprietary compounds to demonstrate that MPA induced diarrhea can be prevented by blocking the activity of a bacterial enzyme in the intestinal microbiome responsible for generating a toxic form of MPA in the lower gut