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。

• 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
• 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' 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

 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（由适用提供）：该提案的目的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氏病（AD）的神经保护剂药物。当前，FDA批准的AD干预措施是有限效率的症状治疗方法，不会影响AD病因或改变疾病进展的过程。这是针对针对AD病理生理学的新型AD治疗的临界需求。最近的研究暗示了神经炎性细胞因子TNF-A是与神经退行性病理学的关键介体。多次临床前和临床研究表明，TNFA是修改AD进展过程的“可吸毒”分子靶标。初步研究表明，我们的铅化合物IDT在体外显示了潜在的TNFA抑制作用。我们的1阶段SBIR研究表明，在三重转基因（3XTG）AD小鼠模型中，每天口服的低剂量IDT显着改善了认知功能。 IDT还调节了脑TNFA蛋白水平，并停止了相关的神经病理学的进展，包括通过免疫组织染色评估，包括Aß斑块和神经缠结。尽管使用IDT进行了长期的口服治疗方案，但未观察到发病率，死亡率或任何明显的副作用。综上所述，这些数据强烈表明我们的铅化合物是出色的抗AD候选药物。拟议的第2阶段SBIR研究旨在实现两个目标。首先，我们希望进行IDT作为研究新药（IND）应用所需的FDA安全和毒理学研究，该应用将在批准后允许其在人类中使用（AIMS 1-4）。其次，我们的效率数据表明，IDT在较低剂量下可能更有效。 AIM 5将优化3xtgad小鼠较低剂量的IDT剂量效能感反应。目标1：评估IDT遗传毒性。目标2：评估IDT救济，分布，代谢和极端（ADME）目标3：评估三项研究中的口服IDT安全药理学：AIM 4：评估大鼠的重复IDT剂量毒性。 AIM 5：评估3XTG AD小鼠中的下IDT剂量。