A Novel Small Molecule TNF-alpha Inhibitor as a Disease-Modifying Alzheimer's Disease Drug Treatment

一种新型小分子 TNF-α 抑制剂作为缓解阿尔茨海默病药物治疗的药物

• 批准号: 9466541
• 负责人: SOMASUNDAR PRASAD GABBITA
• 金额: $ 69.69万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9466541
• 关键词: ADME Study; Acute; Address; Adverse effects; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Area; Award; Back; Brain Neoplasms; Canis familiaris; Cardiovascular system; Characteristics; Chronic; Clinical; Clinical Research; Cognition; Data; Development Plans; Disease; Disease Progression; Dose; Drug Targeting; Elements; Etiology; Excretory function; FDA approved; Failure; Frontotemporal Dementia; Functional disorder; Future; Goals; Grant; Guidelines; Human; In Vitro; Intervention; Investigational Drugs; Investigational New Drug Application; Lead; Licensing; Measures; Mediator of activation protein; Metabolism; Molecular Target; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neuroprotective Agents; No-Observed-Adverse-Effect Level; Oral; Oryctolagus cuniculus; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase III Clinical Trials; Pilot Projects; Preparation; Proteins; Publishing; Rattus; Readiness; Reporting; Research; Safety; Small Business Innovation Research Grant; Staining method; Stains; Suggestion; Symptoms; TNF gene; Telemetry; Therapeutic; Thioflavin S; Toxicology; Transgenic Organisms; Treatment Protocols; absorption; base; clinical development; cognitive function; cytokine; developmental toxicology; drug candidate; drug development; efficacy study; factor A; good laboratory practice; improved; inhibitor/antagonist; meetings; metabolic abnormality assessment; mortality; mouse model; neuroinflammation; neuropathology; novel; pre-clinical; preclinical study; safety study; safety testing; small molecule; symptom treatment; tau phosphorylation; trend; tumor necrosis factor-alpha inhibitor

ABSTRACT The goal of this proposal is to develop tumor necrosis factor α (TNFα)-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-α as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNFα is a “druggable” molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNFα inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNFα inhibitor administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. Our compound also modulated brain TNFα protein levels and halted the progress of AD-associated neuropathology including Aß plaques and neurofibrillary 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 our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed studies are following up on recently awarded phase 2 SBIR where we are performing several key FDA-required IND studies. The proposed CRP grant studies will build on the phase 2 SBIR studies to lead to an IND submission. Key Aims include large animal safety toxicology studies and preparation for Pre-IND meeting with the FDA.

抽象的 该建议的目的是开发肿瘤坏死因子α（TNFα）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批准的广告 干预措施是有限效率的症状治疗，不影响AD病因或 修改疾病进展的过程。这是对新颖的广告处理的关键需求 针对AD病理生理学。 最近的研究暗示神经炎性细胞因子TNF-α是AD-的关键介体 相关的神经退行性病理。多次临床前研究表明 TNFα是一个“可药的”分子靶标，可修饰AD进展过程。 初步研究表明，我们的铅化合物在体外显示了潜在的TNFα抑制作用。 我们的1阶段SBIR研究表明，我们的小分子TNFα抑制剂给药 10个月的每天口头可显着改善三重转基因的认知功能 （3XTG）AD鼠标模型。我们的化合物还调节脑TNFα蛋白水平并停止 广告相关神经病理学的进展，包括Aß斑块和神经纤维缠结 通过免疫组织染色评估。没有发病率，死亡率或任何明显的副作用 尽管与我们的化合物进行了长期的口服治疗方案，但我们仍被观察到。拍摄 总之，这些数据强烈表明我们的铅化合物是一种极好的抗AD药物 候选人。拟议的研究正在跟进最近授予的第二阶段SBIR 正在进行多项FDA需要的IND研究。拟议的CRP赠款研究将 建立在第2阶段SBIR研究的基础上，以导致IND提交。主要目的包括大动物 安全毒理学研究和与FDA预先开会的准备。