DERMAXON LLC — Department of Health and Human Services SBIR Phase I: NIAMS

Description

Project SummaryAbstractPruritusalso called itchis the most frequent dermatological symptom in the US with up toof Americans being affectedPruritic stimuli are detected by a subset of nociceptive neuronspruriceptorswhich fire action potential in response to peripheral activation by THor THmolecules induced by chronic inflammatory skin diseases such as ichthyosisprurigo nodularisand hidradenitis suppurativaT type calcium channels contribute to the firing behavior of itch sensing neurons in synaptic skin nerve terminals and have recently been discovered to mediate calcium entry in immune cellsThis T type calcium channel expression pattern is consistent with their critical roles at detecting itch sensations associated with skin inflammatory diseasesPreliminary work has enabled us to formulate the central hypothesis that topical inhibition of the three T type channel isoforms in the skin will silence action potentialAPdischarge of itch Aand C fibers induced by pruritogenic and inflammatory cytokineswill directly reduce the release of these cytokines by THor THcellsand will lead to improved efficacy and limited systemic exposuretogether reducing the risk of adverse effects compared to systemic treatmentsOur hypothesis is strongly supported by our experimental findingsFirstour lead compoundDXis a potent inhibitor of the three T type channelsCavCavand Cavat sub micromolar levelsSecondtreatment with DXdoes not induce psychoactivity in rodents but profoundly reduces histamine evoked itch in mice after intradermal administrationThirdwe discovered DXa T type blocker that reduces histamine evoked itch after oral administrationFourthwe show for the first time that these two Cav s blockersDXand DXsignificantly reduce the release of THpruritic cytokineILafter human peripheral blood mononuclear cellPBMCactivationand THsynergizing cytokineTNFby activated macrophagesThe overall goal of this collaborative effort between DermaXon s experts in medicinal chemistryimmunologyand dermatology is to demonstrate the technical feasibility of developing inhibitors of skin T type channels as novel therapeutics for the topical treatment of pruritus associated with inflammatory skin diseasesOur objectives in this proposal areAimcomplete the optimization of our first topical T type lead inhibitor DXbased on our previously designed chemotypes and characterize their Cav s activity and selectivityAimcompare the effect of four Cav s blockers selected in SAon proinflammatory and pruritogenic cytokine release by activated immune cellsand assess their safetyAimcompare the anti pruritic efficacy after intra dermal administration of two T type channels inhibitors selected in Aimusing the histamineevoked acute itch and the dry skin chronic itch in vivo modelsThe identification of lead compounds that are active in preclinical acute and chronic itch models will set the stage for a next generation of topical pruritus therapeutics to be used in both adult and pediatric patients suffering from itch associated with inflammatory skin diseasesand will support development of a novel therapeutic topical treatment PROJECT NARRATIVEPublic Health RelevancePruritusalso called itchis associated with chronic inflammatory skin diseases such as ichthyosisprurigo nodularisand hidradenitis suppurativa and is a leading health problem in the U SItch management is currently aimed only at treating inflammationbut pruritus is highly recalcitrant to treatment in some patients due to the relative lack of therapeutics that specifically inhibit pruritusOur objective in this proposal is to design and topically deliver T type calcium channel blockers that will silence action potential discharge induced by pruritogenic cytokines interacting with pruriceptor nerve endingsand at the same timewill reduce the release of inflammatory cytokines by activated immune cellswith improved efficacy and limited systemic exposureThis SBIR Phasewill generate data necessary to validate our proposed targetintradermal T type channelsfor the treatment of itch in adult and pediatric patients