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Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

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Item Type:Article
Title:Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations
Creators Name:Otten, C. and Knox, J. and Boulday, G. and Eymery, M. and Haniszewski, M. and Neuenschwander, M. and Radetzki, S. and Vogt, I. and Hähn, K. and De Luca, C. and Cardoso, C. and Hamad, S. and Igual Gil, C. and Roy, P. and Albiges‐Rizo, C. and Faurobert, E. and von Kries, J.P. and Campillos, M. and Tournier‐Lasserve, E. and Derry, W.B. and Abdelilah-Seyfried, S.
Abstract: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 new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.
Keywords:Angiogenesis, CCM, ERK5, Indirubin-3-Monoxime, KLF2, Animals, Caenorhabditis elegans, Mice, Zebrafish
Source:EMBO Molecular Medicine
Publisher:EMBO Press / Wiley
Page Range:e9155
Date:1 October 2018
Official Publication:https://doi.org/10.15252/emmm.201809155
PubMed:View item in PubMed

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