SBIR-STTR Award

The goal of this proposal 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. P2D, inc. is developing a novel TNF? inhibitor, PD2015 (3,6' dithiothalidomide), a dithionylated analog of thalidomide as an anti-AD drug candidate for in vivo efficacy testing in a mouse model of AD. PD2015 exhibits 1800% greater TNF? inhibition in vitro than its parent, thalidomide. The applicant organization recently published work demonstrating the efficacy of PD2015 in 3xTg AD mice [52]. A 50 mg/kg PD2015 i.p. dose administered daily for two months significantly improved working memory (*P<0.05) in 3xTg AD mice. PD2015 also significantly modulated brain TNF? levels after daily treatment for two months in 3 x Tg AD mice. Recent preliminary studies with chronic oral PD2015 dosing (50 mg/kg) demonstrate improved cognition. In contrast, thalidomide did not improve working memory or block brain TNF? levels in 3 xTg AD mice. Taken together, these data strongly suggest that PD2015 is a good anti-AD drug candidate. The proposed preclinical study is designed to evaluate the oral efficacy of chronic low doses of PD2015 administration across a 12-fold dose range in symptomatic 6 mo. old 3xTg AD mice. Specific Aim 1A): Determine the effect of chronic oral administration of PD2015 on cognitive function in 3xTg AD mice. Specific Aim 1B): Determine the effect of PD2015 on indicators of neuroinflammation and AD- associated pathology including TNF-? levels, Ass1-40/Ass1-42 levels, microglial activation, tau, phospho-tau, synaptophysin, SNAP-25 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 an effective drug that can be taken orally to target the underlying neuroinflammation in AD to modify disease progression and improve cognitive function and block the underlying AD-associated pathology.

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

Project Terms:
Adverse effects; Affect; Age; Alzheimer's Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; amyloid precursor protein processing; analog; Asses; Behavioral; Binding Proteins; Biochemical; Biochemistry; Biological; Brain; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; cognitive function; comparison group; Computer software; Confidential Information; Control Groups; cytokine; Data; design; Disease Progression; Dose; drug candidate; efficacy testing; entorhinal cortex; Enzyme-Linked Immunosorbent Assay; Etanercept; Etiology; Exhibits; FDA approved; Functional disorder; Goals; Hippocampus (Brain); Histology; Human; Immunohistochemistry; improved; In Vitro; in vivo; Individual; inhibitor/antagonist; Inhibitory Concentration 50; Injection of therapeutic agent; Intervention; Knock-out; Learning; Mediator of activation protein; Memory; Messenger RNA; Molecular Target; Monitor; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; neuroinflammation; Neurologic; neuron loss; Neuroprotective Agents; neurotoxic; neurotoxicity; novel; Oral; Oral Administration; Outcome Measure; Parents; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; preclinical study; Process; Proteins; public health relevance; Publishing; Research; S-nitro-N-acetylpenicillamine; Senile Plaques; Short-Term Memory; Small Business Innovation Research Grant; success; Synapses; Synaptophysin; tau Proteins; Techniques; Testing; Thalidomide; TNF gene; Transgenic Organisms; Tumor Necrosis Factor-alpha; tumor necrosis factor-alpha inhibitor; Work

The goal of this proposal 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 shows potent TNF? inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNF? inhibitor administered orally or peripherally significantly improved cognitive function in multiple AD mouse models. Our compound also modulated brain TNF? protein levels, microglial activation, and the progress of AD-associated neuropathology. No morbidity, mortality or any obvious side effects were observed despite long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed SBIR phase 2 grant studies will de-risk further development of our compound by 1) finding a new synthetic method that is viable for commercial manufacturing and 2) performing key early safety toxicology studies in preparation for future FDA-required IND enabling studies.

Public Health Relevance Statement:
PROJECT NARRATIVE Alzheimer’s 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:
Address; Adverse effects; Affect; age related; Alzheimer's Disease; Amyloid beta-Protein; amyloid precursor protein processing; analog; Animal Disease Models; Applications Grants; Binding Proteins; Brain; Brain Neoplasms; Budgets; Canis familiaris; Cardiovascular system; chemical synthesis; Chronic; Clinical; Clinical Research; clinically relevant; Cognitive deficits; cognitive function; cognitive performance; complement C2a; cytokine; Data; design; Development; Disease Progression; Dose; drug candidate; Drug Targeting; entorhinal cortex; Etanercept; Etiology; executive function; Exhibits; factor A; FDA approved; Functional disorder; Funding; Future; Genes; genotoxicity; Goals; Grant; Hepatocyte; Hippocampus (Brain); Histopathology; Human; Immune signaling; improved; In Vitro; in vivo; Infection; inhibitor/antagonist; Injections; Intervention; Kilogram; Knock-out; Lead; Learning; man; Mediator of activation protein; Memory; Messenger RNA; metabolic profile; Metabolism; Methods; Microglia; Microsomes; Molecular Target; Morbidity - disease rate; mortality; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; neuroinflammation; Neurologic; neuron loss; neuropathology; Neuroprotective Agents; neurotoxic; neurotoxicity; NF-kappa B; novel; Oral; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; phase 2 study; preclinical study; Preparation; Procedures; Progress Reports; Proteins; Rattus; Readiness; Research; research clinical testing; Rest; Risk; Rodent Model; Route; Safety; Senile Plaques; Small Business Innovation Research Grant; small molecule; success; symptom treatment; Synapses; tau Proteins; tau-1; Telemetry; Testing; Thalidomide; TNF gene; Toxicokinetics; Toxicology; Transgenic Organisms; Treatment Protocols; tumor necrosis factor-alpha inhibitor