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病（AD）的神经保护药物。目前 FDA 批准的 AD 干预措施是对症治疗，疗效有限，不会影响 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。 最近的研究表明神经炎症细胞因子 TNF-¿ 是 AD 相关神经退行性病理学的关键介质。多项临床前和临床研究表明，TNF 是一种“可成药”的分子靶点，可以改变 AD 的进展过程。 P2D 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，用于 AD 小鼠模型的体内功效测试。 PD2015 的体外 TNF 抑制作用比其母体沙利度胺高 1800%。申请组织最近发表了证明 PD2015 在 3xTg AD 小鼠中的功效的工作 [52]。 50 mg/kg PD2015 腹膜内注射两个月内每天给药的剂量显着改善了 3xTg AD 小鼠的工作记忆 (*P<0.05)。在 3 x Tg AD 小鼠中每日治疗两个月后，PD2015 还显着调节脑 TNF 水平。最近长期口服 PD2015 剂量（50 mg/kg）的初步研究表明认知能力有所改善。相比之下，沙利度胺没有改善 3 xTg AD 小鼠的工作记忆或阻断脑 TNF 水平。总而言之，这些数据强烈表明 PD2015 是一种很好的抗 AD 候选药物。拟议的临床前研究旨在评估在有症状的 6 个月内，在 12 倍剂量范围内长期低剂量服用 PD2015 的口服疗效。老 3xTg AD 小鼠。 具体目标 1A)：确定长期口服 PD2015 对 3xTg AD 小鼠认知功能的影响。具体目标 1B)：确定 PD2015 对 3xTg AD 小鼠中神经炎症和 AD 相关病理指标的影响，包括 TNF-¿ 水平、Ass1-40/Ass1-42 水平、小胶质细胞激活、tau、磷酸化 tau、突触素、SNAP-25。