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Humanization of a Notch 3 Agonist Antibody for Pre-Clinical Development of a CADASIL Treatment
Organization SCHEPENS EYE RESEARCH INSTITUTELocation BOSTON, UNITED STATESPosted 15 Jan 2021Deadline 31 Dec 2025 ⚠️
NIHUS FederalResearch GrantFY2025Ab responseAdventitial CellAgonistAmino AcidsAnatomic SitesAnatomic structuresAnatomyAnimal ModelAnimal Models and Related StudiesAntibodiesAntibody FormationAntibody ProductionAntigensApoplexyAreaArterial DisorderArteriesArteriopathyAutopsyBBB crossingBindingBinswanger DiseaseBinswanger EncephalopathyBioavailabilityBiologicalBiological AvailabilityBiological MarkersBiometricsBiometryBiostatisticsBloodBlood - brain barrier anatomyBlood Cell CountBlood Cell NumberBlood PlasmaBlood Reticuloendothelial SystemBlood VesselsBlood-Brain BarrierBody TissuesBrainBrain Nervous SystemBrain Vascular AccidentCell BodyCell Communication and SignalingCell DeathCell LineCell SignalingCell SurvivalCell ViabilityCellLineCellsCerebral StrokeCerebrovascular ApoplexyCerebrovascular StrokeCerebrumChemistryChronic Progressive Subcortical EncephalopathyClinicalClinical Treatment MoabCollaborationsComplementarity Determining RegionsComplimentarity Determining RegionComputer ModelsComputerized ModelsDNA mutationDataDevelopmentDoseDrosophila Homolog of NOTCH 3Drug KineticsELISAEncephalonEnzyme-Linked Immunosorbent AssayExternal DomainExtracellular DomainEyeEyeballFDA approvedFramework RegionsGeneral HospitalsGenesGenetic ChangeGenetic defectGenetic mutationGenetics-MutagenesisGoalsHemato-Encephalic BarrierHereditaryHistopathologyHu-mABsHumanHypervariable LoopHypervariable RegionsHypoxiaHypoxicImmunoglobulin Hypervariable RegionIn VitroIn vivo analysisIndividualInheritedIntracellular Communication and SignalingKO miceKnock-out MiceKnockout MiceLeadLeiomyocyteLinkLuciferase ImmunologicLuciferasesMediatingMembraneMiceMice MammalsMicrovascular DysfunctionModalityModern ManMolecular InteractionMonoclonal AntibodiesMurineMusMutagenesisMutagenesis Molecular BiologyMutationNOTCH3NOTCH3 geneNeurologistNull MouseOxygen DeficiencyPb elementPenetrationPericapillary CellPericytesPerivascular CellPharmacokineticsPhasePhysiologic AvailabilityPlasmaPlasma SerumPreclinical TestingPredispositionProductionProteinsPublishingReceptor ProteinReporterResearch InstituteReticuloendothelial System, Serum, PlasmaRouget CellsSignal TransductionSignal Transduction SystemsSignalingSkeletal MuscleSmooth Muscle CellsSmooth Muscle MyocytesSmooth Muscle Tissue CellStrains Cell LinesStrokeSubcortical Arteriosclerotic EncephalopathySubcortical InfarctionsSubcortical InfarctsSubcortical LeukoencephalopathySusceptibilityTechnologyTestingTherapeuticTissue ArraysTissue ChipTissue MicroarrayTissuesToxic effectToxicitiesTransgenic MiceVascular Cognitive ImpairmentVascular DiseasesVascular DisorderVascular Smooth MuscleVoluntary Muscleaminoacidantibody biosynthesisautosomebio-markersbiologicbiologic markerbiological signal transductionbiomarkerblood vessel disorderblood-brain barrier crossingbloodbrain barrierbloodbrain barrier crossingbrain attackcardiac disease induced cognitive impairmentcell preparationcerebralcerebral vascular accidentcerebrovascular accidentcerebrovascular contribution to cognitive impairmentcerebrovascular contribution to cognitive impairment and dementiacerebrovascular contributions to cognitive dysfunctioncomputational modelingcomputational modelscomputer based modelscomputerized modelingcross reactivitycultured cell linedevelopmentaldosageefficacy studyenzyme linked immunoassaygenome mutationheavy metal Pbheavy metal leadhumAbshuman mAbshuman modelhuman monoclonal antibodieshuman monoclonalshuman tissuehumanized antibodyimmunogenimmunoglobulin biosynthesisin vitro Assayin vivoin vivo evaluationin vivo testingloss of functionmAbsmanufacturabilitymanufacturemembrane structuremicrovascular complicationsmicrovascular diseasemodel of animalmodel of humanmonoclonal Absmouse modelmurine antibodymurine modelnecrocytosisnecropsynotchnotch proteinnotch receptorsnovelpostmortempre-clinicalpre-clinical developmentpre-clinical efficacypre-clinical testingpreclinicalpreclinical developmentpreclinical efficacypreservationpreventpreventingpulmonaryreceptorsmall vessel diseasestable cell linestrokedstrokessubcutaneoussubdermaltargeted drug therapytargeted drug treatmentstargeted therapeutictargeted therapeutic agentstargeted therapytargeted treatmenttherapeutic agent developmenttherapeutic developmentvascularvascular and cognitive impairmentvascular cognition impairmentvascular cognitive declinevascular cognitive diseasevascular cognitive disordervascular cognitive dysfunctionvascular cognitive impairment and dementiavascular contribution to impairment or dementiavascular contributions to cognition/dementiavascular contributions to cognitive declinevascular contributions to cognitive decline and dementiavascular contributions to cognitive impairmentvascular contributions to cognitive impairment and dementiavascular disease and impaired cognitionvascular dysfunctionvascular dysfunction resulting in cognitive declinevascular related cognitive declinevascular related cognitive impairmentvasculopathy
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PROJECT SUMMARY
Notch 3 mutations are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), a small vessel disease characterized by stroke and vascular
cognitive impairment. Transgenic mouse studies from our lab and others have shown that Notch 3 sig-
naling is critical for mural cell…
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