Anti-fibrotic therapy for primary sclerosing cholangitis

Anti fibrotic therapy for primary sclerosing cholangitis AbstractPrimary sclerosing cholangitisPSCis a rare and severe condition in which chronic bile duct injury leads to liver fibrosisCurrentlythere are no approved therapeutics for PSCand the only definitive cure is liver transplantHencean urgent need exists to find effective treatmentsparticularly interventions that can preventreduceand potentially reverse liver fibrosisHrelaxinserelaxinacts on the G protein coupled receptorGPCRRelaxin Family Peptide ReceptorRXFPto mediate vasodilatory and cardioprotective effects in patients with acute heart failureAHFHoweverthe long term beneficial effects of serelaxin in AHF are likely related to its strong anti fibrotic effects that have been shown in animal models of multiple diseases involving fibrosisincluding cardiacpulmonaryrenaland hepaticRecent data suggest that serelaxin may be a promising treatment for diseases characterized by fibrosisDespite its enormous potentialserelaxin has a short half life in vivois difficult to synthesizeand cross reacts with the related receptorRXFPIn additionthe cAMP mediated actions of serelaxin may be associated with deleterious long term effectsTo address these limitationswe have identified a novel B chain only peptide variant of serelaxinBwhich is RXFPspecific and ameliorates fibrosis via cell specific effects on fibroblastsBis less expensive to manufactureand as a single chain peptide is also far easier to functionalize to improve its stability and in vivo efficacyWe have prepared a lipidated Bwith an extended plasma half lifeBis the first single chain insulin like peptide having a selective signaling profile that favors the anti fibrotic actions of serelaxinbut with minimal cAMP related effectsThe overall goal of this project is to develop and characterize Bas an innovative treatment for PSCIn Phasewe will confirm biological activity in vitro and evaluate Bin a small animal model of PSCSignificant attenuation of fibrosis in the animal model will merit submission of a PhaseapplicationPhasework will focus on obtaining the preclinical data necessary for submission of an INDPharmacokinetics and toxicity studiesas well as animal studies to demonstrate efficacywill be performed NarrativePrimary sclerosing cholangitisPSCis a progressive chronic liver disease characterized by hepatic inflammation and fibrosis that lead to multifocal biliary stricturesPSC is closely associated with inflammatory bowel disease that is present in a majority of the patientsMost patients will require liver transplantationwhich is often not curative due to disease recurrenceThere is no approved treatment for PSCdespite recent advances in understanding the cause of the diseaseThe purpose of this proposal is to develop a new therapy for PSC with a novel mechanism of action to prevent fibrosis