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

描述(申请人提供)：这项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的病因或改变疾病的进展过程。因此，迫切需要一种针对AD病理生理学的新的AD治疗方法。最近的研究表明，神经炎性细胞因子肿瘤坏死因子-β是AD相关神经退行性病变的关键介质。多项临床前和临床研究表明，肿瘤坏死因子是一种“可用药”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的肿瘤坏死因子抑制剂PD2015(3，6‘-二硫代硫代多胺)，这是一种沙利度胺的二硫代化类似物，可作为抗AD药物的候选药物，用于AD小鼠模型的体内疗效测试。PD2015在体外对肿瘤坏死因子的抑制作用比其母体沙利度胺高1800%。申请组织最近发表了一项工作，展示了PD2015在3xTg AD小鼠中的疗效[52]。50 mg/kg PD2015 ip.连续两个月每天给药显著改善3xTg AD小鼠的工作记忆(P&lt；0.05)。在每日治疗两个月后，PD2015也显著调节了3x Tg AD小鼠的脑内肿瘤坏死因子水平。最近对慢性口服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3xTg AD小鼠的工作记忆或阻断脑内肿瘤坏死因子的水平。综上所述，这些数据强烈表明PD2015是一个很好的抗AD药物候选药物。这项拟议的临床前研究旨在评估慢性低剂量PD2015在有症状的6个月内12倍剂量范围内的口服疗效。老年3xTg AD小鼠。具体目的1)：观察长期口服PD2015对3xTg AD小鼠认知功能的影响。具体目的1B)：测定PD2015对3xTg AD小鼠神经炎症指标和AD相关病理指标的影响，包括肿瘤坏死因子-β水平、As1-40/As1-42水平、小胶质细胞活化、tau蛋白、磷酸化tau蛋白、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.