Novel Targeting of the S1P Receptor, S1P1, and Nox4 as Therapeutic Approaches in ARDS

PROJECT SUMMARYAcute Respiratory Distress SyndromeARDSis a devastating syndrome that afflicts more thanpatients in United States alone and has an unacceptably high mortality rate ofCurrently there are no therapies that address the loss of lung vascular barrier integrityvascular leakage and alveolar flooding that are critical features of ARDS pathobiologyThe PI was the first to demonstrate that sphingosinephosphateS Pa multifunctional lipid mediatoris an effective therapy for reducing vascular leakage in inflammatory lung injury via ligation of S P receptorS Pa G protein coupled S P receptor highly expressed in lung vascular endothelial cellsECsWe demonstrated that S Preceptor ligation by S P or a long acting phosphonated S P analogueTySIPonaterapidly stimulates a signaling cascade that reorganizes the lung EC cytoskeletonenhances junctional integrity and decreases lung vascular permeabilityIntravenous administration of S P or TySIPonate reduces murine and canine lung vascular hyper permeability evoked by ventilator induced lung injuryVILIbacterial endotoxinLPSischemia reperfusionradiationor traumatic brain death with marked improvement alveolar edema formationIn additionthis STTR team of investigators have demonstrated that lung vascular permeability in ARDS is directly related to excessive generation of reactive oxygen speciesROSROS are key contributors to lung inflammation and injury with a key role for the ROS generating enzymeNADPH oxidaseNoxa critical mediator of inflammatory lung injury in preclinical models of VILI and ARDSThe goal of this STTR Phase I application is to formulate theReStore Liposomean ACE antibody conjugated liposome that encargoes the combination of TySIPonate and a novel Noxsmall molecule inhibitorNoxsmiSpecific AimSpecific Aimwill evaluate in vitro effects of the ReStore Liposome on vascular permeability and ROS generation and Specific Aimwill evaluate in vivo effects of the ReStore Liposome in murine preclinical models of ARDS VILI models of lung injury as a prelude to use as a therapeutic intervention to reduce the morbidity and mortality of ARDS in humansAs there is an acute unmet need for novel therapies against ARDSthe academicUniversity of Arizonaprivate biotech partnershipRestore TherapeuticsLLCwill leverage unparalleled expertise in drug deliveryinflammatory lung injury and ROS biochemistry to reduce both lung vascular permeability and ROS burden to effectively attenuate preclinical and human ARDS pathobiology PUBLIC HEALTH RELEVANCEAcute Respiratory Distress SyndromeARDSis a devastating syndrome that afflicts more thanpatients in United States alone and has the unacceptable high mortality rate ofThe loss of lung endothelial cellECbarrier integrityresulting in vascular leakage and alveolar floodingis a critical feature of the pathobiology of ARDS and is directly related to excessive generation of reactive oxygen speciesROSThereforethere an acute need exists for novel therapies against ARDS that target the leaky lung vasculature and attenuates the untoward effects of ROSThis STTR seeks to utilize a novel combination therapeutic strategy to reduce ARDS morbidity and mortality