Targeting integrin outside-in signaling for treating sepsis

In severe sepsissystemic inflammation induced by infection leads to vascular leakagedisseminated intravascular coagulationDICmicrovascular thrombosismultiple organ dysfunctionhemorrhage and circulatory collapseresulting in high mortalityAlthough antibiotics and standard care regimens are helpfulthey are ultimately ineffective for a significant percentage of patientsDespite years of intensive researchthe only new drug approved by the FDA for treatment of severe sepsis is the recombinant activated protein CAPCXigriswhich inhibits thrombin generationprevents thrombosis and reduces inflammationHoweverXigris also causes hemorrhagewhich outweighed its benefits and resulted in its withdrawal from the marketThusthere is an urgent unmet need for new life saving treatment of sepsisIn this applicationwe propose to develop a new drug for sepsis treatmentwhich potently inhibits both intravascular thrombosis and inflammation but does not cause bleedingThis innovative drug targets a novel integrin signaling mechanism recently discovered in the lab of Xiaoping Duco investigator of this applicationGong et al ScienceShen et alNatureShen MBoCwho demonstrated that integrin outside in signaling requires direct interaction between the G protein subunit Gaand an ExE motif conserved in the cytoplasmic domain of several integrin b subunitsincluding bin platelets and bin leukocytesIntegrin mediated cell adhesion and signaling are important in thrombosis and inflammationFurthermoreinhibition of Gaintegrin interaction abolishes outside in signaling without affecting the ligand binding function of integrins important for hemostasisThuswe designed a selective peptide inhibitor of Gabinding ExE motif that potently inhibits occlusive intravascular thrombosis without causing excessive bleedingShen et alNatureImportantlyin preliminary studies using the CLP modeltreatment of mice with the ExE motif peptide potently inhibits inflammation and thrombosis in septic micesignificantly reducing their mortalityWe are thus submitting this Phase I SBIR grant with the following Specific AimsPharmacologically characterize ExE motif peptide inhibitors for protective effects in CLPendotoxin and bacteria induced sepsis modelsDetermine the vascular safety of ExE motif peptides by evaluating their effects on vascular leakage and bleedingBased on the outcomes of Aimsanddevelop novel high loading peptide nanoparticlesHLPNfor efficiet in vivo deliveryThe proposed work will provide the first steps in developing a novel drug that simultaneously targets two important pathological aspects of sepsisthrombosis and excess inflammationwithout impairing hemostasis and vascular integrityThis innovative strategy has the potential to significantly advance the therapeutic benefit of sepsis treatment!Sepsiswhich afflictsU Spatients year at a cost of$billionhas a high mortality rate ofresulting from excessive inflammationthrombosis and vascular leakage hemorrhageHoweveranti inflammatory drugsthus farare not effective in treating sepsisand the bleeding risk of anti thrombotic drugs outweighs their beneficial effectsWe propose to develop a peptide based new drug that has combined anti inflammatory and antithrombotic effects without increasing bleeding riskand develop high loading peptide nanoparticlesHLPNfor efficient drug delivery