دورية أكاديمية
أعرض في EDS

omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.

التفاصيل البيبلوغرافية
العنوان: omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases.
المؤلفون: Alvarado CX; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA., Makarious MB; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK., Weller CA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA., Vitale D; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA., Koretsky MJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA., Bandres-Ciga S; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA., Iwaki H; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Levine K; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA., Singleton A; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Faghri F; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Nalls MA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA., Leonard HL; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA; Data Tecnica LLC, Washington, DC 20037, USA; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20814, USA; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address: hampton@datatecnica.com.
المصدر: American journal of human genetics [Am J Hum Genet] 2024 Jan 04; Vol. 111 (1), pp. 150-164.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
مواضيع طبية MeSH: Alzheimer Disease*/drug therapy , Alzheimer Disease*/genetics , Neurodegenerative Diseases*/drug therapy , Neurodegenerative Diseases*/genetics , Parkinson Disease*, Humans ; Community Resources ; Multiomics ; Mendelian Randomization Analysis
مستخلص: Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (p SMR_multi  < 2.95 × 10 -6 and p HEIDI  > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community.
Competing Interests: Declaration of interests C.X.A., D.V., K.L., H.L.L., F.F., and M.A.N. declare that they are consultants employed by Data Tecnica International, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. M.A.N. is also an advisor to Neuron23, Inc. and Character Biosciences.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
التعليقات: Update of: medRxiv. 2023 Jul 14:2023.04.06.23288266. doi: 10.1101/2023.04.06.23288266. (PMID: 37090611)
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معلومات مُعتمدة: Z01 AG000949 United States ImNIH Intramural NIH HHS; ZIA AG000534 United States ImNIH Intramural NIH HHS; ZIA NS003154 United States ImNIH Intramural NIH HHS
فهرسة مساهمة: Keywords: SMR; druggability; neurodegeneration; summary-data-based Mendelian randomization
تواريخ الأحداث: Date Created: 20240105 Date Completed: 20240112 Latest Revision: 20240725
رمز التحديث: 20240726
مُعرف محوري في PubMed: PMC10806756
DOI: 10.1016/j.ajhg.2023.12.006
PMID: 38181731
قاعدة البيانات: MEDLINE
الوصف
تدمد:1537-6605
DOI:10.1016/j.ajhg.2023.12.006