加州大学Marina Sirota小组宣布他们研制了细胞类型导向的网络校正联合治疗阿尔茨海默病。相关论文于2025年7月21日发表在《细胞》杂志上。
为了解决这个问题，研究组引入了一种基于人类数据和现实世界证据的细胞类型特异性多靶点药物发现策略。这种方法整合了单细胞转录组学、药物干扰数据库和临床记录。在这个框架下，来曲唑和伊立替康被确定为一种潜在的联合治疗，分别针对神经元和神经胶质细胞中AD相关基因表达的变化。在具有Aβ和tau沉积的AD无主题模型中，与载药和单药治疗相比，该联合治疗显着改善了记忆表现并减少了AD相关病理。单核转录组学分析证实，该疗法以细胞类型特异性的方式逆转了疾病相关的基因网络。这些结果突出了细胞类型导向的联合疗法在治疗多因素疾病（如AD）方面的前景，并为针对患者特异性转录组学和临床特征的精准医学奠定了基础。
据悉，阿尔茨海默病（AD）是一种多因素神经退行性疾病，其特征是在不同细胞类型中发生异质性分子变化，这给治疗开发带来了重大挑战。
附：英文原文
Title: Cell-type-directed network-correcting combination therapy for Alzheimer’s disease
Author: Yaqiao Li, Carlota Pereda Serras, Jessica Blumenfeld, Min Xie, Yanxia Hao, Elise Deng, You Young Chun, Julia Holtzman, Alice An, Seo Yeon Yoon, Xinyu Tang, Antara Rao, Sarah Woldemariam, Alice Tang, Alex Zhang, Jeffrey Simms, Iris Lo, Tomiko Oskotsky, Michael J. Keiser, Yadong Huang, Marina Sirota
Issue&Volume: 2025-07-21
Abstract: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.
DOI: 10.1016/j.cell.2025.06.035
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00737-8