Preclinical Testing of Human Ghrelin and Growth Hormone for Sepsis in the Elderly

PROJECT DESCRIPTIONThis SBIR Phase II proposal is intended to further develop human ghrelinhGhrand human growth hormonehGHas a combination therapy for elderly patients with sepsis and septic shockIn the USmore than one million people develop sepsis every yearand nearlyof septic deaths occur in patients older thanyears of ageCurrentlyno effective pharmacotherapy exists for the treatment of sepsisOne of the reasons for sepsis clinical trial failures is that the preclinical evaluation of anti sepsis drug candidates has been conducted exclusively in young animalsRat Ghrfor exampleameliorates sepsis in youngbut not agedratsWe have discovered that administration of GH upregulates the expression of the Ghr receptor and restores Ghr s responsiveness in aged animals with sepsisIn our completed SBIR Phase I projectco administration of hGhr and hGHhGhr hGHsignificantly ameliorated sepsis associated lungliverand kidney injury in septic aged animalsWe further demonstrated that the combination therapy nearly doubled the survival rate of septic aged ratsMoreoverboth hGhr and hGH have been clinically tested and used for other indications with an excellent safety profileBased on our Phase I resultswe hypothesize that hGhr hGH can be further developed as an effective therapy for sepsis in the elderlyTo advance hGhr hGH therapy towards its clinical use against sepsis in the elderlywe plan to determine the combination therapy s most effective dose and therapeutic window to attenuate tissue injury and improve survivalWe will also study hGhr hGH s combination effects on safety and pharmacokineticsPKFinallywe will conduct an exploratory study in an ovine model of sepsis to evaluate hGhr hGH s effects on hemodynamic parameters and organ injuryThese proposed studies should provide crucial information for the future filing of an IND application to further develop hGhr hGH in clinical trialsOur ultimate goal is to obtain FDA approval for the use of hGhr hGH as a safe and effective treatment for elderly patients with sepsis and septic shock PUBLIC HEALTH RELEVANCE STATEMENTSepsis is a major cause of death in the United Statesbut there is no effective FDA approved treatment for sepsisAttempts to treat sepsis have failedin partbecause new treatments are only tested in sepsis models with young animalswhile most patients with sepsis are at leastyears oldWe have shown that treatment with a combination of two human hormonesghrelin and growth hormoneimproves sepsis outcomes in aged animalsWe plan to further develop this combination therapy toward its future approval by the FDA as a new treatment for elderly patients with sepsis and septic shock