Development of Nasal IGF-1 as a Migraine Therapeutic

Summary AbstractMigraine is an immense healthcare burdenExisting therapeutics are only fractionally effective since they may not adequately target underlying key causesCNS hyperexcitabilityHEand oxidative stressOSBrain HE enhances OS and OS in turn promotes brain HEincluding that seen in the trigeminal systemTSa site involved in migraine painUnraveling this vicious cycle may lead to novel therapeutics for migraineOur unique breakthrough came from research showing that increased physical and intellectual activityEEreduces OS and lowers susceptibility to spreading depressionSDa model of migraine that begins with HE and includes nociceptive HE in the TSHuman studies show that EE also reduces susceptibility to migraine while EE in animals prompts a rise in insulin like growth factorIGFwhich is neuroprotectiveWe are developing IGFas a novelnaturally occurring migraine treatment since it reduces the HEOS needed to trigger SDand by extension we reason the HEOS that occurs in the TS with migraine modelsThe General Goal of this proposal is to define the optimal IGFdose in rats necessary to mitigate the TS activation that accompanies migraineand is evident in our modelsto inform subsequent translation to human clinical trialsTwo models of migraine will be used to validate our therapeutic approachBoth will examine the impact of nasal administration IGFon nociceptive activation of the TSThe project has two specific aimsAIMDetermine the dose range of IGFneeded to mitigate migraine modeled in rats using SDmodelIGFwill be giveneveryrd day forweeksvia intranasal delivery and the impact on neocortical SD thresholdSDTand related TS activationi ec fosOS and CGRP levelswill be determinedMilestoneDetermine the optimal dose of IGFthat mitigates migraine modeled in female and male ratsThis data will provide the basis for selection of doses to be tested in subsequent toxicology studies to enable human clinical trials to determine if nasal IGFcan control migraine in human patientsAIMDetermine the dose range of IGFneeded to mitigate migraine modeled in rat via intravenous glyceryltrinitrateGTNinfusionmodelIGFwill be administeredeveryrd day forweeksvia intranasal delivery and impact on TS activationsee abovewill be measured laterfollowingminutes of intravenous GTN infusionMilestoneValidation in a second translational model and determine the dose of intranasally administered IGFnecessary to mitigate migraine in male and female ratsThis data will provide secondary support for subsequent plans for the enablement of IND enabling studies needed for clinical trialsThis project is significant because it has high commercial value due to unmet needs of migraineurs and it is likely to establish the technical merit and feasibility of development of IGFas a migraine therapeuticDevelopment of IGFas a migraine remedy is innovativeas it is a naturally occurring EE based signaland is likely to work upstream of calcitonin gene related peptideCGRPa known trigger of migraine Project narrative Migraine is an immense healthcare burden that costs $billion a year in the United States alone with only partially effective therapeuticsperhaps because none adequately impact root causes of migrainebrain hyperexcitability and oxidative stressWeat Seurat TherapeuticsIncare developing nasal insulin like growth factorIGFas a novel therapeutic for migraine since it reduces the hyperexcitability and oxidative stress otherwise needed to evoke migraineand is highly effective in initial preclinical trialsHerewe seek to obtain dose response data in two migraine models to inform subsequent dosing for human clinical trialsthese tasks will advance IGFtoward clinical developmentFDA registrationand commercialization as a novel treatment for migraines