The use of selective NaV1.7 inhibitors to treat inflammation post-surgery

ABSTRACTNonsteroidal anti inflammatory drugsNSAIDsare the most commonly prescribed drugs to treat posttraumatic inflammation and painalthough they carry significant risk of seriousdose dependent adverse eventsCorticosteroidswhich are an alternative class of anti inflammatory drugsare rarely prescribed for post traumatic inflammationdue to adverse effects on wound healing and their lack of specificityThusthere is a great need for novel anti inflammatory therapies with better safety profilesThere is also a great medical need for novelsafe anti inflammatory compounds that also have analgesic propertiesNaVis an ion channel that is expressed on primary nociceptorswhere they mediate painEvidence suggests that NaVis also expressed on dendritic cells of the immune systemwhere their function is yet unknownChromocell created a novel class of analgesic compoundsCCand structural analogsthat selectively block NaVand are currently FDA fast tracked in clinical trials to treat painAs we show withinin a surgical incision model of pain and inflammationrats treated with CChad markedly reduced paw edema and accelerated resolution of the edemaAnother analogCCis currently completing Phase I human safety trialsIn the rat surgical incision modelCCwas administered to animals fordays and fully resolved edema indays compared todays with IbuprofenCCalso reduced inflammatory cell infiltration of the pancreas and reduced systemic levels of the pro inflammatory cytokineTNFaWithin this projectwe will characterize the anti inflammatory effects of CCin the rat surgical incision modelas well as in vitro using PBMCsIf our hypothesis is correctthen CCwill be a first in class analgesic drug to treat post surgical inflammation and pain by selectively targeting the peripheralinactivated NaVchannelSpecific AimDetermine local anti inflammatory effects of CCin the rat surgical incision modelThe goal of this aim is to provide molecular or cellular evidence to explain the observed reduction in edema with our NaVinhibitors and suggest possible mechanisms of actionWe will assess inflammatory parameters within the pawincludingalocal levels of inflammatory mediatorsbinfiltration of immune cell subsetschistological assessment of tissue structure and the formation of granulation bedsanddchanges in NaVexpressionSpecific AimDetermine systemic anti inflammatory effects of CCin surgical incision rat modelIn this aimwe will determine effects on inflammatory parameters in bloodincludingacirculating levels of inflammatory mediators andbproportions of circulating immune cell subsetsSpecific AimStudy effect of CCon human PBMC cytokine secretion in vitroWe will study the effect of CCon inflammatory markers excreted by cultured human PBMCs with and without LPS stimulationCytokines secreted into the media will be measured by multiplexed immunoassaysMilestonesObservation of a statistically significant decrease in proinflammatory cytokines and an increase in anti inflammatory cytokines in the paw and to a lesser extent systemically NARRATIVE In its most extreme forminflammation can lead to organ death and sepsisNonsteroidal anti inflammatory drugsNSAIDsand Corticosteroids are both significantly limited in terms of benefit due to many clinical related issues including seriousdose dependent adverse eventsadverse effects on wound healing and lack of specificityIf this project is successful then CCwill be a first in class analgesic drug to treat post surgical inflammation by selectively targeting the peripheralinactivated NaVchannel