一种新型小分子 TNF-α 抑制剂作为缓解疾病的 AD 药物治疗。-猫眼课题宝

一种新型小分子 TNF-α 抑制剂作为缓解疾病的 AD 药物治疗。

批准号：

9134606

负责人：

SOMASUNDAR PRASAD GABBITA

金额：

$74.46万

依托单位：

P2D, INC.

依托单位国家：

美国

项目类别：

财政年份：

2015

资助国家：

美国

项目状态：

已结题

起止时间：

2015-09-01 至 2017-09-14

来源：

https://reporter.nih.gov/project-details/9134606

关键词：

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

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DESCRIPTION (provided by applicant): 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.

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