P2D Bioscience is developing a first-in-class treatment for Alzheimers disease (AD). Our drug is an orally-effective combination that targets both innate immunity and the dopamine transport (DAT) inhibitor. Recent studies suggest that TNF? and DAT inhibitors are orally effective treatments for AD in preclinical AD transgenic mouse models.The proposed studies will determine if our compound is an effective treatment for AD using a three transgenic animal models of AD. The rationale is rigorously evaluation for our lead compound across different models of AD pathology in this limited direct-to-phase 2 SBIR application. The proposed specific aims will determine if chronic oral treatment significantly improves AD symptoms and AD /FTD pathophysiology in these animal models.Aim 1 : Determine the brain and plasma PK profile of our dual acting lead compound to aid in developing a PKPD correlation.Aim 2: Determine the efficacy of chronic daily oral treatment of our dual acting lead compound at improving cognitive/behavioral function in three transgenic models of dementia and their AD-associated pathology
Public Health Relevance Statement: PROJECT NARRATIVE Alzheimers Disease (AD) is a significant neurological problem affecting nearly 5 million of our senior U.S. citizens. The present research aims to develop a compound that targets the underlying neuroinflammation in AD to modify disease progression and improve cognitive function.
Project Terms: Oral Administration ; Oral Drug Administration ; intraoral drug delivery ; Affect ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Analysis of Variance ; ANOVA ; Variance Analyses ; Transgenic Animals ; inhibitor/antagonist ; inhibitor ; Anxiety ; Astrocytes ; Astrocytus ; Astroglia ; astrocytic glia ; Automobile Driving ; driving ; Autopsy ; necropsy ; postmortem ; Behavior ; Benztropine ; Benzatropine ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Brain ; Brain Nervous System ; Encephalon ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Cells ; Cell Body ; Cocaine ; Decision Making ; Dialysis procedure ; Dialysis ; dialysis therapy ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Dopamine ; Hydroxytyramine ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Equilibrium ; balance ; balance function ; foot ; Foundations ; frontal lobe ; frontal cortex ; Future ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; Natural Immunity ; Innate Immunity ; Native Immunity ; Non-Specific Immunity ; Nonspecific Immunity ; In Vitro ; Incidence ; Interleukin-1 beta ; Beta Proprotein Interleukin 1 ; IL-1 beta ; IL-1 β ; IL-1-b ; IL-1β ; IL1-Beta ; IL1-β ; IL1B Protein ; IL1F2 ; IL1β ; Interleukin 1beta ; Interleukin-1β ; Preinterleukin 1 Beta ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Learning ; Memory ; Methods ; Motivation ; Mus ; Mice ; Mice Mammals ; Murine ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Neurotransmitters ; Nerve Transmitter Substances ; Nucleotides ; Pathology ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Publishing ; Research ; Rewards ; Safety ; Stains ; Staining method ; Telemetry ; Telemetries ; Tissues ; Body Tissues ; Toxicology ; Generations ; Measures ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; Ï Proteins ; Mediating ; Outcome Measure ; dopamine transporter ; DAT dopamine transporter ; improved ; Chronic ; Solid ; Clinical ; Phase ; Biochemical ; Neurologic ; Neurological ; Microdialysis ; Microglia ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; Evaluation ; Stimulus ; Disease Progression ; analog ; uptake ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Therapeutic ; cognitive function ; Immunes ; Immune ; Oral ; Amentia ; Dementia ; Neurocognitive ; interest ; transport inhibitor ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; transgenic ; Transgenic Organisms ; MEFV gene product ; pyrin ; marenostrin ; novel ; Pathogenesis ; Reporting ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Pharmacodynamics ; Modeling ; response ; drug development ; Adverse effects ; Bioavailable ; Molecular Interaction ; Binding ; Brain region ; small molecule ; Apoptosis-Related Cysteine Protease Caspase 1 ; CASP-1 ; CASP1 ; Caspase-1 ; Caspase-1 Gene ; ICE Protease ; IL-1 beta Convertase ; IL-1 beta-Converting Enzyme ; IL-1BC ; IL-1b Converting Enzyme ; IL1B-Convertase ; IL1BC ; IL1BCE ; Interleukin 1-B Converting Enzyme ; Interleukin 1-Beta Convertase ; Interleukin-1 Beta Converting Enzyme ; Interleukin-1 Converting Enzyme ; CASP1 gene ; Address ; Dose ; Symptoms ; Data ; Cognitive ; Leucine-Rich Repeat ; Right-Handed Beta-Alpha Superhelix ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Transgenic Model ; transgenic trait ; Development ; developmental ; Behavioral ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; approach behavior ; neuroinflammation ; neuroinflammatory ; AD transgenic mice ; Alzheimer's disease transgenic mice ; Alzheimer's transgenic mice ; Tg2576 ; Prevalence ; abeta accumulation ; abeta aggregation ; amyloid beta accumulation ; amyloid beta aggregation ; amyloid β accumulation ; amyloid β aggregation ; aβ accumulation ; aβ aggregation ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; therapeutic target ; 3xTg-AD mouse ; 3xTg ; 3xTg-AD mice ; FDA approved ; effective therapy ; effective treatment ; phase 2 study ; phase II study ; mild cognitive impairment ; mild cognitive disorder ; Drug Targeting ; incentive salience ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; frontotemporal degeneration ; Frontal Temporal Lobar Degeneration ; Alzheimer's disease patient ; Alzheimer's patient ;