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来自轻度阿尔茨海默病1期衰老细胞溶解试验的探索性液体生物标志物评估。

Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease.

作者信息

Garbarino Valentina R, Palavicini Juan Pablo, Melendez Justin, Barthelemy Nicolas R, He Yingxin, Kautz Tiffany F, Lopez-Cruzan Marisa, Mathews Julia J, Xu Peng, Zhang Bin, Saliba Afaf, Ragi Nagarjunachary, Sharma Kumar, Mason Dallin, Johnson Samuel, Hendrix Suzanne, Craft Suzanne, Petersen Ronald C, Espindola-Netto Jair Machado, Xue Ailing, Tchkonia Tamara, Kirkland James L, Salardini Arash, Musi Nicolas, Bateman Randall J, Gonzales Mitzi M, Orr Miranda E

机构信息

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA.

出版信息

Neurotherapeutics. 2025 Apr 23:e00591. doi: 10.1016/j.neurot.2025.e00591.


DOI:10.1016/j.neurot.2025.e00591
PMID:40274471
Abstract

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D ​+ ​Q), in older adults (N ​= ​5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability. Herein, we present exploratory analyses of senescence and AD-associated analytes in blood, cerebrospinal fluid (CSF) and urine from this study in effort to guide biomarker development for future senolytic trials. Immunoassays, mass spectrometry and transcriptomics were performed and changes in analyte levels were assessed from baseline to post-treatment using paired t-tests. Targeted cytokine and chemokine analyses revealed increases in plasma fractalkine and MMP-7 and CSF IL-6 from baseline to post-treatment. Mass spectrometry indicated stable levels of amyloid β and tau proteins in CSF, unchanged urinary metabolites, and modest treatment-associated lipid profile changes. Targeted transcriptomic analysis of peripheral blood mononuclear cells indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. The levels and treatment responses of the analytes identified here may help inform trial design and outcomes for senolytic studies. Independent validation will be necessary to develop standardized biomarker panels across senolytic trials for AD. ClinicalTrials.gov: NCT04063124.

摘要

衰老细胞的积累会促使包括阿尔茨海默病(AD)在内的与年龄相关疾病的进展。专注于细胞衰老的临床试验尚处于早期阶段,尚未建立反映衰老细胞负担或对衰老细胞裂解剂(清除衰老细胞的疗法)反应的可靠结果指标。衰老细胞裂解剂达沙替尼加槲皮素(D + Q)在患有早期AD的老年人(N = 5)中的首次开放标签试验结果表明,达沙替尼可穿透中枢神经系统,且安全性和耐受性良好。在此,我们对该研究中血液、脑脊液(CSF)和尿液中的衰老及AD相关分析物进行探索性分析,以指导未来衰老细胞裂解剂试验的生物标志物开发。进行了免疫测定、质谱分析和转录组学分析,并使用配对t检验评估了从基线到治疗后分析物水平的变化。靶向细胞因子和趋化因子分析显示,从基线到治疗后,血浆中 fractalkine和MMP-7以及脑脊液中IL-6有所增加。质谱分析表明脑脊液中淀粉样β蛋白和tau蛋白水平稳定,尿液代谢物未发生变化,且治疗相关的脂质谱有适度改变。对外周血单核细胞的靶向转录组分析表明,包括FOS、FOSB、IL1β、IL8、JUN、JUNB、PTGS2在内的炎症基因下调。此处鉴定出的分析物水平及其治疗反应可能有助于为衰老细胞裂解剂研究的试验设计和结果提供信息。有必要进行独立验证,以开发适用于AD衰老细胞裂解剂试验的标准化生物标志物组。ClinicalTrials.gov:NCT04063124。

相似文献

[1]
Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer's disease.

Neurotherapeutics. 2025-4-23

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[2]
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[3]
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[4]
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