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

描述（由申请人提供）：本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干预措施是疗效有限的对症治疗，不影响AD的病因或改变疾病进展的过程。因此，迫切需要一种针对阿尔茨海默病病理生理的新型阿尔茨海默病治疗。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的关键介质。多项临床前和临床研究表明，TNF¿是一种“可药物化”的分子靶点，可以改变阿尔茨海默病的进展过程。P2D, inc.正在开发一种新的TNF抑制剂PD2015 (3,6' dithiothalidomide)，这是一种沙利度胺的二硫酰化类似物，作为抗AD的候选药物，用于在AD小鼠模型中进行体内疗效测试。PD2015对肿瘤坏死因子的抑制作用比母体沙利度胺高1800%。申请机构最近发表了一项研究，证明PD2015对3xTg AD小鼠b[52]的有效性。每天给药50 mg/kg PD2015，连续两个月显著改善3xTg AD小鼠的工作记忆（*P<0.05）。PD2015在3 Tg AD小鼠每日治疗两个月后也显著调节脑TNF -水平。最近的初步研究表明，慢性口服PD2015剂量（50 mg/kg）可改善认知。相比之下，沙利度胺不能改善3xtg AD小鼠的工作记忆或阻断脑TNF -水平。综上所述，这些数据强烈表明PD2015是一种良好的抗阿尔茨海默病候选药物。拟议的临床前研究旨在评估慢性低剂量PD2015在12倍剂量范围内口服对症状性6岁3xTg AD小鼠的疗效。特异性目的1A)：确定慢性口服PD2015对3xTg AD小鼠认知功能的影响。特异性目的1B)：确定PD2015对3xTg AD小鼠神经炎症和AD相关病理指标的影响，包括TNF-¿水平、Ass1-40/Ass1-42水平、小胶质细胞活化、tau、磷酸化tau、突触素、SNAP-25。

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.