Peptide therapies for treating CF lung inflammation

Abstract Lung disease is the major cause of morbidity and mortality in cystic fibrosisCFpatientsHerea viscous cycle of infection and inflammation lead to persistent neutrophilia and bronchiectasis that destroy the lungOne of the cornerstones of a comprehensive treatment plan is the use of anti inflammatory drugsWhile the significance of anti inflammatory treatments was realized in thesthere remains a dearth of drug therapies aimed toward treating the powerful and relentless inflammation in CF patientsCorticosteroidsused during pulmonary exacerbationshave positive effects and improve CF pathophysiologysuch as reducing mucus and edemainhibiting chemotaxis and adhesionand activating leukocytesCorticosteroids are not effective for long term use due to their extensive side effectsNonethelessanti inflammatories remain an attractive option for the treatment of CF lung diseaseOraiis a plasma membrane Cachannel that is expressed in the lung and plays in key role in mediating inflammationFor exampleactivation of Oraioccurs during store operated CaentrySOCEwhich in airway epithelia triggers secretion of the neutrophil chemoattractant ILThereforeinhibition of Oraiis an attractivedrugable targetYet to dateno anti Oraitherapies existShort Palate LUng and Nasal epithelial CloneSPLUNCis a secreted protein that is highly expressed in the lung and is thought to play a critical role in maintaining lung healthSPLUNCis abundant in broncho alveolar lavagesuggesting that it plays a role in the innate defense of the lower airwaysImportantlywe have recently discovered that SPLUNCnegatively regulates OraiThusour data indicate that SPLUNCinhibits store operated CaentrySOCEand has the potential to reduce CF inflammationIndeedSPLUNCknockout mice have a hyperinflammatory lung phenotype and SPLUNCprotein is absent from CF patient s BALWe have identified the active site within SPLUNCthat regulates Oraiand a peptide corresponding to this regioncalledinhibits Oraiin an equipotent fashion as full length SPLUNCand is anti inflammatory in an allergic mouse modelIn this studywe propose to develop novelpeptide analogues that reduce inflammation by inhibiting Oraidependent Cainflux and to test them in murine chronic CF infection modelsThere are no current effective anti inflammatories for CFso this constitutes a novel approachIn additionthis is the first therapeutic that targets OraiFurthermoreseveral inflammatory cells will be tested for inflammation control usingand its mutants Narrative One of the cornerstones of a comprehensive treatment plan for CF patients is the use of antiinflammatory drugsWhile the significance of anti inflammatory treatment was realized in thesthere remains a dearth of drug therapies aimed toward treating the powerful and relentless inflammation in CF patientsWe propose to develop a stable peptidewhich reduces inflammation by regulating the Oraidependent influx of Caand delivers the therapeutic by inhalation