A first-in-class orally active anti-TNF-alpha inhibitor to treat AD

治疗 AD 的一流口服活性抗 TNF-α 抑制剂

• 批准号: 8592209
• 负责人: SOMASUNDAR PRASAD GABBITA
• 金额: $ 39.55万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592209
• 关键词: Adverse effects; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Asses; Behavioral; Binding Proteins; Biochemical; Biochemistry; Biological; Brain; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Computer software; Confidential Information; Control Groups; Data; Disease Progression; Dose; Enzyme-Linked Immunosorbent Assay; Etanercept; Etiology; Exhibits; FDA approved; Functional disorder; Goals; Hippocampus (Brain); Histology; Human; Immunohistochemistry; In Vitro; Individual; Inhibitory Concentration 50; Injection of therapeutic agent; Intervention; Knock-out; Learning; Mediator of activation protein; Memory; Messenger RNA; Molecular Target; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neuroprotective Agents; Oral; Oral Administration; Outcome Measure; Parents; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Process; Proteins; Publishing; Research; S-nitro-N-acetylpenicillamine; Senile Plaques; Short-Term Memory; Small Business Innovation Research Grant; Synapses; Synaptophysin; TNF gene; Techniques; Testing; Thalidomide; Transgenic Organisms; Tumor Necrosis Factor-alpha; Work; amyloid precursor protein processing; analog; cognitive function; comparison group; cytokine; design; drug candidate; efficacy testing; entorhinal cortex; improved; in vivo; inhibitor/antagonist; mouse model; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; novel; preclinical study; public health relevance; success; tau Proteins; tumor necrosis factor-alpha inhibitor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该提案的目标是开发肿瘤坏死因子 ¿ (TNF) 抑制化合物作为治疗阿尔茨海默氏病 (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，不会影响 AD 病因或改变疾病进展过程，因此存在迫切需要。针对 AD 病理生理学的新型 AD 治疗方法最近的研究表明神经炎症细胞因子 TNF-¿多项临床前和临床研究表明 TNF 是 AD 相关神经退行性病理学的关键介质。是一种改变 AD 进展过程的“可药物”分子靶标，公司正在开发一种新型 TNF¿抑制剂，PD2015（3,6' 二硫沙利度胺），沙利度胺的二硫酰化类似物，作为抗 AD 候选药物，在 AD 小鼠模型中进行体内功效测试，其 TNF 水平高出 1800%。申请人组织最近发表的研究表明，PD2015 在 3xTg AD 小鼠中的疗效显着改善，每天腹腔注射 50 mg/kg PD2015，持续两个月。 ）在 3xTg AD 小鼠中，PD2015 也显着调节脑 TNF¿最近对 3 x Tg AD 小鼠进行长期口服 PD2015 给药（50 mg/kg）的初步研究表明，沙利度胺并不能改善工作记忆或阻断脑 TNF 水平。综合起来，这些数据强烈表明 PD2015 是一种良好的抗 AD 药物候选药物，该临床前研究旨在评估长期低剂量 PD2015 给药在 12 倍剂量范围内的口服疗效。在有症状的 6 个月老 3xTg AD 小鼠中。具体目标 1A)：确定长期口服 PD2015 对 3xTg AD 认知功能的影响。具体目标 1B)：确定 PD2015 对神经炎症和 AD 相关病理指标（包括 TNF-¿）的影响3xTg AD 小鼠中的 Ass1-40/Ass1-42 水平、小胶质细胞激活、tau、磷酸化 tau、突触素、SNAP-25。