SBIR-STTR Award

The goal of this application is to develop tumor necrosis factor ¿ (TNF¿)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer's disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-¿ as a key mediator in AD-associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF¿ is a "druggable" molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound, IDT, shows potent TNF¿ inhibition in vitro. Preliminary Studies also demosntrate that 100 mg/kg IDT administered orally every day for two months significantly improved working memory in the triple-transgenic (3xTg) AD mouse model. IDT also modulated brain TNF¿ protein levels after daily treatment for two months in AD mice. No morbidity, mortality or any obvious side effects were observed despite the long-term daily treatment regiment with IDT. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed preclinical study is designed to evaluate the oral efficacy of IDT in 9-month old 3xTg AD mice which mimic moderate symptoms and pathology. Aim 1: Determine the effect of oral administration of IDT mixed in diet on cognitive performance in 3xTg AD mice. Aim 2: Determine the effect of the IDT on TNF-¿ levels, Ass1-40/Ass1-42 levels, microglial activation, synaptophysin and degenerating neurons in 3xTg AD mice.

Public Health Relevance:
Alzheimer's Disease (AD) is a significant neurological problem affecting 4.5 million of our senior U.S. citizens. The present research aims to develop an effective drug that can be taken orally to target the underlying neuroinflammation in AD to modify disease progression and improve cognitive function.

Public Health Relevance Statement:
Alzheimer's Disease (AD) is a significant neurological problem affecting 4.5 million of our senior U.S. citizens. The present research aims to develop an effective drug that can be taken orally to target the underlying neuroinflammation in AD to modify disease progression and improve cognitive function.

NIH Spending Category:
Aging; Alzheimer's Disease; Brain Disorders; Cancer; Neurodegenerative; Neurosciences

Project Terms:
Adverse effects; Affect; Age; Alzheimer's Disease; Amyloid beta-Protein; amyloid precursor protein processing; arm; Asses; Behavior; Binding Proteins; Biochemical; Brain; Chronic; Clinical; Clinical Research; Cognitive; Cognitive deficits; cognitive function; cohort; Confidential Information; Control Groups; cytokine; Data; design; Diet; Disadvantaged; Disease; Disease model; Disease Progression; Dose; drug candidate; Drug Delivery Systems; Drug Kinetics; entorhinal cortex; Enzyme-Linked Immunosorbent Assay; Etanercept; Etiology; Evaluation; FDA approved; feeding; frontal lobe; Functional disorder; Goals; Hippocampus (Brain); improved; In Vitro; inhibitor/antagonist; Injection of therapeutic agent; Intervention; Knock-out; Lead; Learning; Legal patent; macromolecule; Measures; Mediator of activation protein; Memory; Messenger RNA; Molecular Target; Morbidity - disease rate; morris water maze; Mortality Vital Statistics; Motivation; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; neuroinflammation; Neurologic; neuron loss; Neurons; Neuroprotective Agents; neurotoxic; novel; Oral; Oral Administration; Outcome Measure; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; preclinical study; Proteins; Radial; Research; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Senile Plaques; Short-Term Memory; Small Business Innovation Research Grant; small molecule; Spinal Injections; Staging; success; Symptoms; Synapses; Synaptophysin; tau Proteins; Testing; Thalidomide; TNF gene; Transgenic Organisms; Tumor Necrosis Factor-alpha

The goal of this proposal is to develop tumor necrosis factor a (TNFa)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer's disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-a as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNFa is a "druggable" molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound, IDT, shows potent TNFa inhibition in vitro. Our Phase 1 SBIR studies demonstrate that a low dose of IDT administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. IDT also modulated brain TNFa protein levels and halted the progress of AD- associated neuropathology including Aß plaques and neurofibrally tangles as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects were observed despite the long-term oral daily treatment regimen with IDT. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed Phase 2 SBIR studies are designed to achieve two goals. First, we want to conduct the FDA safety and toxicology studies required for submission of IDT as an Investigational New Drug (IND) application which would allow its use in humans when approved (Aims 1-4). Second, our efficacy data suggests IDT may be more effective at an even lower dose. Aim 5 will optimize IDT dose-efficacy response at lower doses in 3xTgAD mice. Aim 1: Assess IDT genotoxicity. Aim 2: Assess IDT absorption, distribution, metabolism and excretion (ADME) Aim 3: Assess oral IDT safety pharmacology in three studies: Aim 4: Assess repeated IDT dose toxicity in rats. Aim 5: Assess lower IDT doses in 3xTg AD mice.

Public Health Relevance Statement:


Public Health Relevance:
Alzheimer's Disease (AD) is a significant neurological problem affecting 4.5 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.

NIH Spending Category:
Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Dementia; Neurodegenerative; Neurosciences

Project Terms:
absorption; Acute; Address; Adverse effects; Affect; Alzheimer's Disease; Ames Assay; Amyloid; Amyloid beta-Protein; amyloid precursor protein processing; Brain; Canis familiaris; Cardiovascular system; Cells; Chromosome abnormality; Chronic; Clinical; Clinical Research; Clinical Trials; clinically significant; cognitive function; cytokine; Data; Disease; Disease Progression; Dose; drug candidate; Drug Kinetics; Drug or chemical Tissue Distribution; Equilibrium; Etiology; Evaluation; Excretory function; Failure (biologic function); FDA approved; Functional disorder; genotoxicity; Goals; Guidelines; Hepatocyte; Human; Immune; Immune system; Impaired cognition; improved; In Vitro; in vivo; inhibitor/antagonist; Intervention; Investigational Drugs; Investigational New Drug Application; Lead; male; man; Manuscripts; Maximum Tolerated Dose; Measures; Mediator of activation protein; meetings; Metabolic; Metabolism; Molecular Target; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; neuroinflammation; Neurologic; neuron loss; neuropathology; Neuroprotective Agents; neurotoxic; neurotoxicity; novel; Oral; Oral Administration; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; phase 1 study; Phase III Clinical Trials; preclinical study; Progress Reports; Proteins; public health relevance; Radioactivity; Radiolabeled; radiotracer; Rattus; Reporting; Research; Research Design; respiratory; response; Safety; Senile Plaques; Small Business Innovation Research Grant; small molecule; Staining method; Stains; Symptoms; Synapses; tau phosphorylation; tau Proteins; Testing; Therapeutic; Therapeutic Index; Thioflavin S; Toxic effect; Toxicology; Transgenic Organisms; Treatment Protocols; Tumor Necrosis Factor-alpha