GABAeron, Inc. — Department of Health and Human Services SBIR Phase I: NIA

Description

PROJECT SUMMARYFAST TRACK APPLICATIONAlzheimer s diseaseADis a neurodegenerative disorder affecting overmillion individuals in the United States aloneCarriers of apolipoproteinapoEone of the three apoE isoformsapoEapoEapoEare associated withof all AD casesmaking apoEthe major genetic risk factor for ADAs a complex disease that causes early damage to the hippocampusa brain region essential for cognitionAD presents unique challenges for developing traditional therapiesTo dateall efforts to develop therapies that target specific AD related pathways have failed in human trials of late stage ADAs a resultan emerging consensus in the field is that treatment of patients with mild or moderate AD with current drugs comes too latelikely due to significant neuronal loss in the brainespecially in the hippocampusIn this regardinduced pluripotent stem cellsiPSCsprovide a way to generate human neurons or their progenitors for cell replacement therapyHowevercurrently limited iPSC based therapeutic approaches under development for potential AD treatment do not consider apoEs impactwhich could lead to clinical failure due to patient heterogeneity and or apoEs detrimental effectsBy using apoEallelic expression to stratify patientswe will be able to create a defined patient populationapoEpositive AD patientsfor testing a matched disease modifying treatmenthuman iPSC derived somatostatinSSTpositive GABAergic interneurons with an apoEgenotypeThis proposal builds on five novel findings from our recent studies in animal models of AD and in human iPSC derived neuronsFirstapoEcauses SST GABAergic interneuron loss in the hippocampal hiluswhich correlates with the impairment of hippocampal network activity and the extent of learning and memory deficitsSecondapoEcauses the selective death of human iPSC derived SST GABAergic interneurons in cultureThirdthe detrimental effect of apoEon SST GABAergic interneurons is cell autonomousFourthtransplantation of mouse GABAergic interneuron progenitors into the hippocampal hilus restores normal learning and memory in aged apoEknock inapoEKImice without or with AaccumulationFifthtransplantation of human iPSCderived GABAergic interneuron progenitors into the hippocampal hilus restores normal learning and memory in aged apoEKI miceThe goals of this proposal areto develop and optimize a protocol for the robust derivation of SST GABAergic interneurons from human iPSCs with an apoEgenotypeto determine the desired dose and test the safety and efficacy of transplanting human iPSC derived SST GABAergic interneurons into the hippocampal hilus to restore normal learning and memory in aged apoEKI miceandto test the safety and efficacy of transplanting human iPSC derived SST GABAergic interneurons into the hippocampal hilus to restore normal learning and memory in apoEKI mice expressing human amyloid precursor proteinAPPwith mutations that cause familial ADFADhAPPFADPROJECT NARRATIVE The goals of this proposal are to develop and optimize a protocol for the robust derivation of somatostatinSSTpositive GABAergic interneurons from human induced pluripotent stem cellsiPSCsand to determine the desired dose and test the safety and efficacy of transplanting human iPSC derived SST GABAergic interneurons into the hippocampus to restore normal learning and memory in aged apoEknock in mice without or with amyloid accumulation!