Cargando…

omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases

Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer’s Disease, highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is ag...

Descripción completa

Detalles Bibliográficos
Autores principales: Alvarado, Chelsea X., Makarious, Mary B., Weller, Cory A., Vitale, Dan, Koretsky, Mathew J., Bandres-Ciga, Sara, Iwaki, Hirotaka, Levine, Kristin, Singleton, Andrew, Faghri, Faraz, Nalls, Mike A., Leonard, Hampton L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120805/
https://www.ncbi.nlm.nih.gov/pubmed/37090611
http://dx.doi.org/10.1101/2023.04.06.23288266
_version_ 1785029246797742080
author Alvarado, Chelsea X.
Makarious, Mary B.
Weller, Cory A.
Vitale, Dan
Koretsky, Mathew J.
Bandres-Ciga, Sara
Iwaki, Hirotaka
Levine, Kristin
Singleton, Andrew
Faghri, Faraz
Nalls, Mike A.
Leonard, Hampton L.
author_facet Alvarado, Chelsea X.
Makarious, Mary B.
Weller, Cory A.
Vitale, Dan
Koretsky, Mathew J.
Bandres-Ciga, Sara
Iwaki, Hirotaka
Levine, Kristin
Singleton, Andrew
Faghri, Faraz
Nalls, Mike A.
Leonard, Hampton L.
author_sort Alvarado, Chelsea X.
collection PubMed
description Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer’s Disease, 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’s disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson’s disease, and 9 Progressive supranuclear palsy 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 AD. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [https://nih-card-ndd-smr-home-syboky.streamlit.app/].
format Online
Article
Text
id pubmed-10120805
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-101208052023-04-22 omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases Alvarado, Chelsea X. Makarious, Mary B. Weller, Cory A. Vitale, Dan Koretsky, Mathew J. Bandres-Ciga, Sara Iwaki, Hirotaka Levine, Kristin Singleton, Andrew Faghri, Faraz Nalls, Mike A. Leonard, Hampton L. medRxiv Article Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer’s Disease, 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’s disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson’s disease, and 9 Progressive supranuclear palsy 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 AD. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [https://nih-card-ndd-smr-home-syboky.streamlit.app/]. Cold Spring Harbor Laboratory 2023-07-14 /pmc/articles/PMC10120805/ /pubmed/37090611 http://dx.doi.org/10.1101/2023.04.06.23288266 Text en This article is a US Government work.
spellingShingle Article
Alvarado, Chelsea X.
Makarious, Mary B.
Weller, Cory A.
Vitale, Dan
Koretsky, Mathew J.
Bandres-Ciga, Sara
Iwaki, Hirotaka
Levine, Kristin
Singleton, Andrew
Faghri, Faraz
Nalls, Mike A.
Leonard, Hampton L.
omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title_full omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title_fullStr omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title_full_unstemmed omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title_short omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
title_sort omicsynth: an open multi-omic community resource for identifying druggable targets across neurodegenerative diseases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120805/
https://www.ncbi.nlm.nih.gov/pubmed/37090611
http://dx.doi.org/10.1101/2023.04.06.23288266
work_keys_str_mv AT alvaradochelseax omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT makariousmaryb omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT wellercorya omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT vitaledan omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT koretskymathewj omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT bandrescigasara omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT iwakihirotaka omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT levinekristin omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT singletonandrew omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT faghrifaraz omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT nallsmikea omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases
AT leonardhamptonl omicsynthanopenmultiomiccommunityresourceforidentifyingdruggabletargetsacrossneurodegenerativediseases