Journal Article

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

Abdelilah‐Seyfried, Salim, Knox, Jessica, Eymery, Mathias, Haniszewski, Marta, Faurobert, Eva, Hähn, Kristina, Cardoso, Cécile, Igual Gil, Carla, Tournier‐Lasserve, Elisabeth, Otten, Cécile, Hamad, Sabri, Radetzki, Silke, Neuenschwander, Martin, Vogt, Ingo, Roy, Peter, Derry, W Brent, Boulday, Gwénola, Campillos, Mónica, Albiges‐Rizo, Corinne, von Kries, Jens P, De Luca, Coralie

2018

Overview

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. Synopsis Currently, the only treatment for cerebral cavernous malformation (CCM) vasculature lesions is surgery. This study by Otten et al establishes a multi‐organismal pharmacological approach to suppress the formation of new lesions or to regress existing ones. Many small molecule compounds alleviating the loss of CCM proteins were identified in suppression screens in C. elegans and zebrafish. DePick, a prediction programme for relevant protein targets of active compounds, was used to identify relevant molecular pathways and CCM‐related drug targets. Indirubin‐3‐monoxime (IR3mo) alleviated the lesion burden in preclinical CCM mouse models. Future experiments with IR3mo will help to unravel the CCM pathobiology. Graphical Abstract Currently, the only treatment for cerebral cavernous malformation (CCM) vasculature lesions is surgery. This study by Otten et al establishes a multi‐organismal pharmacological approach to suppress the formation of new lesions or to regress existing ones.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,Wiley Open Access,John Wiley and Sons Inc,Springer Nature
• Subject: Analysis / angiogenesis / Animal models / Brain / CCM / CCM2 protein / Cell Behavior / Cellular Biology / Central nervous system / Danio rerio / Development Biology / EMBO04 / EMBO28 / EMBO46 / Endothelial cells / Endothelium / ERK5 / Gene expression / indirubin‐3‐monoxime / KLF2 / Life Sciences / Morphogenesis / Neurosurgery / Phenotypes / Quantitative Methods / Research Article / Seizures / Stroke / Sulindac / Surgery / Therapeutic applications