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机器学习确定阿尔茨海默病药物再利用的候选者。

Machine learning identifies candidates for drug repurposing in Alzheimer's disease.

机构信息

Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA.

Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.

出版信息

Nat Commun. 2021 Feb 15;12(1):1033. doi: 10.1038/s41467-021-21330-0.


DOI:10.1038/s41467-021-21330-0
PMID:33589615
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7884393/
Abstract

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.

摘要

针对阿尔茨海默病(AD)的新型治疗方法的临床试验耗费了大量的时间和资源,但结果大多是负面的。将已经获得美国食品和药物管理局(FDA)批准的药物重新用于另一种适应症是一种更快、成本更低的选择。我们提出了 DRIAD(AD 中的药物再利用),这是一个机器学习框架,它可以量化 AD 严重程度(Braak 阶段)的病理学和以基因名称列表编码的分子机制之间的潜在关联。DRIAD 应用于 80 种经 FDA 批准和临床测试的药物对分化的人神经细胞培养物进行扰动所产生的基因列表,生成可能重新定位候选药物的排名列表。对得分最高的药物进行检查,以寻找其靶点之间的共同趋势。我们提出,DRIAD 方法可用于提名药物,这些药物在经过进一步验证和鉴定相关药效生物标志物后,可在临床试验中进行快速评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/77d03109fd2d/41467_2021_21330_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/4bc608ad59d1/41467_2021_21330_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/a19184d7008c/41467_2021_21330_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/ea82a3079480/41467_2021_21330_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/20931d93af09/41467_2021_21330_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/77d03109fd2d/41467_2021_21330_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/4bc608ad59d1/41467_2021_21330_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/a19184d7008c/41467_2021_21330_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/ea82a3079480/41467_2021_21330_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/20931d93af09/41467_2021_21330_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a99e/7884393/77d03109fd2d/41467_2021_21330_Fig5_HTML.jpg

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[3]
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[4]
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[5]
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[6]
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[7]
Federated Target Trial Emulation using Distributed Observational Data for Treatment Effect Estimation.

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[8]
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J Neuroinflammation. 2025-4-25

[9]
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Methods Mol Biol. 2025

[10]
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本文引用的文献

[1]
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Nat Med. 2020-1-13

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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia.

Cell Rep. 2019-10-29

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Nat Med. 2019-10-7

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Evidence of a Causal Association Between Cancer and Alzheimer's Disease: a Mendelian Randomization Analysis.

Sci Rep. 2019-9-19

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Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons.

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Rate of Memory Change Before and After Cancer Diagnosis.

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Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity.

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Protective effect of Tenuifolin against Alzheimer's disease.

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