Potent oral chitotriosidase-1 inhibitors as a novel therapy for sarcoidosis

Abstract Sarcoidosis is a systemic disease with large unmet medical needand unknown causecharacterized by the formation of immune granulomas in various organsmainly the lungs and the lymphatic systemAboutof patients develop a chronic or progressive disease necessitating long term treatmentCurrent therapiesincluding the standard of caresystemic corticosteroidsdo not prolong survival and only have limitedshortterm benefitswith significant side effectsMortalityestimated to occur in up toof patientsis mainly due to respiratory failurewith pulmonary fibrosis a common featureThe overall objective of this project is for OncoArendi TherapeuticsOATto develop an oralsmall molecule chitotriosidaseCHITinhibitor as ast in class medicine for sarcoidosiswith superior clinical benefit and safety compared to current treatmentsCHITis one of two enzymatically active chitinaseswhich have been implicated in several disordersincluding interstitial lung diseasesILDssuch as sarcoidosisStudies have demonstrated elevated levelsandgtfoldof CHITin serum and bronchoalveolar lavage fluidBALFof sarcoidosis patientswhich correlated with disease severityIn preliminary studies we have confirmed the reports of increased serum CHITlevels in sarcoidosis patientsWe have identified proprietary potent and selective oral small molecule inhibitors of CHITsuch as OATThe specific goals of this application areevaluation of the effects of a potent and selective CHITinhibitorOATin the beryllium induced murine model of granulomatous lung diseaseAimand investigation of the levels of CHITin patients with sarcoidosis and evaluation of the role of CHITin the granuloma formation ex vivoAimFor Aimas the pathologies of sarcoidosis and chronic beryllium diseaseCBDare indistinguishableand there are no models of sarcoidosisa model of CBD will be usedSpecificallythe effects of oral OATmg kga potent and selective CHIT inhibitorwill be examined in a humanized mouse model of CBD involving challenge of HLA DPtransgenic animals to beryllium oxideBeOThe following endpoints will be measuredigranulomatous inflammation burden in lungsiiCDcell counts in BALFiiiBe specific T cells in lungs and spleenivlung fibrosisvCHITexpression in lungsvithe pharmacodynamic effects of OATwill be determined by measuring chitinolytic activity in serum and BALFor Aimthe levels and cellular origins of CHITwill be investigated in the BALF and serum from up topatients with sarcoidosis andage matched controlsusing standard enzymaticchitinolytic activitytechniquesAn ex vivo model of multi cellular granuloma formation using human BALF cells from sarcoidosis patients will be utilized to measure CHITexpressionSuccessful completion of the studies in this proposal will lay the foundation for the future development of an orally active selective CHITinhibitorwhich is expected to have improved efficacysafety and tolerability compared to current medicines for sarcoidosis Narrative Chronic and progressive sarcoidosis is a serious systemic disease with significant mortalitythat affects various organsincluding the lungsand for which there is no cure or effective medicinesWe are performing researchincluding the use of diseaserelevant animal models and blood and lung cells from sarcoidosis patientson a new type of oral druga chitinase inhibitorthat has the potential to provide superior medical benefit and improved safety compared to current treatmentsand will increase survival and the quality of life for people with sarcoidosisThe results from the studies outlined in this application will be an important step towards the clinical testing of chitinase inhibitors in sarcoidosis patients