Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study
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DOI：
10.1016/j.ebiom.2018.12.052
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发表时间：
2019-02-01
期刊：
影响因子：
11.1
通讯作者：
Kirkland, James L.
中科院分区：
文献类型：
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作者：
Justice, Jamie N.;Nambiar, Anoop M.;Kirkland, James L.
背景：细胞衰老是驱动年龄相关疾病的关键机制，但尚未在人类中进行靶向治疗。特发性肺纤维化（IPF）是一种进行性、致死性细胞衰老相关疾病。使用达沙替尼加槲皮素（DQ）选择性消融衰老细胞，以评估实施衰老干预的可行性。方法：在IPF参与者（n = 14）中进行间歇性DQ（D：100 mg/天，Q：1250 mg/天，3天/周，持续3周）的双中心开放标签研究，以评估实施衰老干预的可行性。主要终点为计划临床评估的保留率和完成率。次要终点是安全性和功能变化以及报告的健康指标。与衰老相关的分泌表型（SASP）的协会进行了explored.Findings：14例稳定的IPF患者被招募。留存率为100%，无DQ中止; 13/14例受试者完成了计划的临床评估。报告了1起严重不良事件。非严重事件主要为轻度-中度，最常见的是呼吸道症状（共16起事件）、皮肤刺激/瘀伤（n = 14）和胃肠道不适（n = 12）。身体功能评估为6分钟步行距离，4米步态速度，和椅子站立时间显着和临床意义的改善（p <0.05）。肺功能、临床生化、虚弱指数（FI-LAB）和报告的健康状况无变化。DQcirculat.ingSASP因子的影响尚无定论，但在功能变化与SASP相关基质重塑蛋白、microRNA和促炎细胞因子的变化之间观察到相关性（23/48个标记物r >= 0.50）。我们的首次人体开放标签试验支持研究的可行性，并提供了初步证据，证明老年溶解剂可以减轻IPF的身体功能障碍，DQ在老年相关疾病的大型随机对照试验中的应用评价(C)2018作者由爱思唯尔公司出版
Background: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.Methods: A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.Findings: Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and proinflammatory cytokines (23/48 markers r >= 0.50).Interpretation: Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. (C) 2018 The Authors. Published by Elsevier B.V.