Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

  • Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals newCerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.show moreshow less

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Author details:Cecile OttenORCiDGND, Jessica Knox, Gwenola BouldayORCiD, Mathias Eymery, Marta Haniszewski, Martin Neuenschwander, Silke Radetzki, Ingo Vogt, Kristina Haehn, Coralie De Luca, Cecile CardosoORCiD, Sabri Hamad, Carla Igual GilORCiD, Peter Roy, Corinne Albiges-Rizo, Eva FaurobertORCiD, Jens P. von Kries, Monica Campillos, Elisabeth Tournier-LasserveORCiD, William Brent DerryORCiD, Salim Abdelilah-SeyfriedORCiDGND
DOI:https://doi.org/10.15252/emmm.201809155
ISSN:1757-4676
ISSN:1757-4684
Pubmed ID:http://www.ncbi.nlm.nih.gov/pubmed?term=30181117
Title of parent work (English):EMBO molecular medicine
Publisher:Wiley
Place of publishing:Hoboken
Publication type:Article
Language:English
Date of first publication:2018/09/04
Completion year:2018
Release date:2021/09/14
Tag:CCM; ERK5; KLF2; angiogenesis; indirubin-3-monoxime
Volume:10
Issue:10
Number of pages:17
Funding institution:transnational E-RARE grant "CCMCURE"; excellence cluster REBIRTH; E-RARE [ERL 138397]; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR) [PJT 153000]; ARC LRCC; ANRFrench National Research Agency (ANR); [SFB958]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
DDC classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Peer review:Referiert
Publishing method:Open Access / Gold Open-Access
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