A Novel Small molecule TNF-alpha inhibitor as a disease-modifying AD drug treatment.

一种新型小分子 TNF-α 抑制剂作为缓解疾病的 AD 药物治疗。

基本信息

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
起止时间：
2015-09-01 至 2017-09-14
项目状态：
已结题

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

项目摘要

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.

描述（由申请人提供）：该提案的目标是开发肿瘤坏死因子 a (TNFa) 抑制化合物作为治疗阿尔茨海默病 (AD) 的神经保护药物，目前 FDA 批准的 AD 干预措施是疗效有限的对症治疗。不影响 AD 病因或改变疾病进展过程因此，迫切需要一种针对 AD 病理生理学的新型 AD 治疗方法，表明神经炎症细胞因子 TNF-a 是一种关键介质。多项临床前和临床研究表明，TNFa 是改变 AD 进展过程的“可药物”分子靶标。我们的先导化合物 IDT 在体外显示出有效的 TNFa 抑制作用。 SBIR 研究表明，连续 10 个月每天口服低剂量 IDT 可显着改善三重转基因 (3xTg) AD 小鼠模型的认知功能，IDT 还可调节大脑 TNFa。通过免疫组织学染色评估，尽管长期每日口服 IDT，但未观察到发病率、死亡率或任何明显的副作用。强烈建议我们的先导化合物是一种优秀的抗 AD 候选药物。拟议的 2 期 SBIR 研究旨在实现两个目标，首先，我们希望进行提交所需的 FDA 安全性和毒理学研究。 IDT 作为一种研究性新药 (IND) 申请，一旦获得批准，将允许其在人类中使用（目标 1-4）。其次，我们的疗效数据表明，目标 5 在更低剂量下可能会更有效。 - 3xTgAD 小鼠中较低剂量的功效反应目标 1：评估 IDT 遗传毒性目标 2：评估 IDT 吸收、分布、代谢和排泄 (ADME) 目标。 3：在三项研究中评估口服 IDT 安全药理学：目标 4：评估大鼠重复 IDT 剂量毒性。目标 5：评估 3xTg AD 小鼠的较低 IDT 剂量。