临床前研究表明,衰老细胞在多个器官系统中的积累与年龄相关。新的证据表明tau蛋白积累,这与阿尔茨海默病和其他tau病的认知能力下降密切相关,驱动大脑中的细胞衰老。在tau蛋白病小鼠模型中药理学清除衰老细胞可减少脑发病机制。与载体处理的小鼠相比,间歇性抗衰老给药减少了tau积累和神经炎症,保存的神经元和突触密度,恢复了异常的脑血流,减少心室扩大。间歇性给药senoletics,达沙替尼联合槲皮素,在其他衰老相关疾病的临床研究中显示出可接受的安全性。有了这些数据,我们提出并在此描述了临床先锋研究的目标和方法。这项最初的开放标签临床试验在五名患有早期阿尔茨海默病的老年人中试行了达沙替尼联合槲皮素的间歇性抗衰老联合疗法。主要目的是通过分析基线和治疗12周后收集的脑脊液来评估达沙替尼和槲皮素的中枢神经系统渗透。Further,通过一系列次要结果指标来评估衰老化合物和阿尔茨海默病相关认知的目标参与,功能,和物理结果,我们将收集有关安全的初步数据,可行性,和功效。这项研究的结果将被用来告知一个随机的发展,双盲,安慰剂对照多中心II期试验,以进一步探索安全性,可行性,和senoletics对调节阿尔茨海默病进展的功效。Clinicaltrials.gov注册号和日期:NCT04063124(2019年8月21日)。
Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer\'s disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer\'s disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer\'s disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer\'s disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).