Novel Treatment For Systemic Effects of Trauma

AbstractNephrilin peptide is a novel designed inhibitor of Rictor complexalso known as mTORCan evolutionarily conserved assembly believed to coordinate cellular stress signalsamong other functionsAs demonstrated in twelve separate rodent studies reported in six published research papers as well as in the data section of this proposalinhibition of Rictor complex by daily subcutaneous bolus administration of nephrilin reverses the effects of stress in numerous animal modelsSpecificallyin burned animalsnephrilin administered beginning two hours after burn injury and continuing for seven days mitigates the loss of glycemic controlkidney function and lean body massand reverses increases in inflammation and sepsis mortalityOne recent study has documented important effects of nephrilin treatment on the rat central nervous system after burn traumaNephrilin treatment following burn injury reverses epigenetic and signaling changes in kidney tissue leading to activation of Raca key component of NADPH oxidaseas well as elevations in markers of oxidative stress such as urinaryisoprostaneSomebut not allof the above effects of nephrilin appear to be influenced by the animalandapos s iron statusAltered iron status has been observed in post trauma human populationsTwenty three grams of nephrilin were manufactured under GMPquality assay methods were developed and validated and the manufactured drug product showed excellent stability overmonths of storageA CMC Section document was writtenAlthough several wound healing products have been approved for use in burn patientsthere is currently no pharmacologic intervention to treat the numerous severe and enduring systemic effects of burn traumaNephrilin is being developed for treatment of burn trauma with a main focus on these important systemic effectsnot wound healingfor which products already existIn Phase I of this SBIR project we will investigate the effect of iron supplementation and nephrilin dosage on the efficacy of nephrilin in a rat scald modelWe will also complete the development of a method for bioassay of nephrilin in biological fluids and a product release bioassay for nephrilin potencyIn Phase IIwe will conduct GLP toxicology studiestransfer and validate methods and aseptic fill and finish of bulk drug substance under cGMP for a future clinical Phase I studyand develop a preliminary protocol for a future Phaseclinical trial Project Narrative Severe burn injury often causes an array of secondary complicationsincluding sepsismetabolic and organ dysfunction and cognitive changesmany of which can last a lifetimeAt present most treatments are palliative and nephrilin is the first new drug to address the underlying epigenetic and signaling disruptions that lead to this vast array of secondary complicationsDevelopment of nephrilin will reduce long term care costs and improve quality of life for victims of serious burns