Long-acting ghrelin for the treatment of ARS

Project Summary The threat of a radiation attack or accident isunfortunatelyall too real and could potentially affect a large enough population so as to overwhelm the medical systemTo be prepared for such an eventit is necessary to stockpile effective radiation medical countermeasuresMCMthat are safeeasily administered to large numbers of peopleand effective even when treatment is delayedhrs after radiation exposureRadiation exposure has the most damaging affects on rapidly dividingundifferentiated cellsAs suchthe bone marrow and epithelium of the gastrointestinal tract are particularly harmed by radiation exposureAcute Radiation SyndromeARSis often divided into subsyndromes based upon the observed symptomsThe hematopoietic sub syndromeH ARSresults in neutropeniaanemiaand thrombocytopeniaDepending upon the speciesdeath can occur withinweeksThe gastrointestinal sub syndromeGI ARSis characterized by cell death in the intestinal epithelium followed by disintegration of the intestinal wall and death from fluid and electrolyte imbalanceintestinal bleeding and sepsisDeath by GI ARS is more rapid than that for H ARSgenerally occurring withindaysOne promising approach that has been shown to treat multiple aspects of ARSbut especially GI ARSis the use of ghrelina peptide hormone produced in the gut which stimulates appetitereverses muscle atrophy in cancerand chemotherapy induced cachexia and other wasting conditionspromotes gut motilityreduces inflammationand restores the health of the intestinal liningBut the use of ghrelin currently requires multiple daily doses due to its poor pharmacokinetic propertiesExtend Biosciences has a platform technology that harnesses the biology of vitamin D to improve the half life and bioavailability of peptidesIn our preliminary workwe have developed a constitutively activelong acting version of ghrelinEXTthat could be administered far less frequently than native ghrelin and may provide improved benefits over native ghrelin for GIARSIn this SBIR Phase I proposalwe will demonstrate the feasibility of our improved ghrelin in ARS efficacy models in mice when given subcutaneouslyhr following exposureOur milestones are to be able to dose less frequently vsnative ghrelinEXTalso has the potential to more effectively mitigate the effects of ARS vsnative ghrelinSelf administration ofdoses of EXTwould better suit the needs of victims of ARS during an emergency than ghrelin alone