Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

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

doi:10.15252/emmm.201809155

Cited by 36 publications

(32 citation statements)

References 86 publications

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“…It has been demonstrated that the three CCM proteins form the CSC, which plays an essential role in the pathogenesis of CCMs when disrupted [26]. Efforts to dissect CSC signaling cascades have been made (Additional file 11) [8,10,[20][21][22][23][24][25][26], but with some contradicting outcomes. It is essential to establish comparative omics methods to assess similarities among those independent studies, which can aid in identification of potential biomarker candidates for prognostic and diagnostic applications.…”

Section: Discussionmentioning

confidence: 99%

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Comparative omics of CCM signaling complex (CSC)

et al. 2020

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Background: Cerebral cavernous malformations (CCMs), a major neurosurgical condition, characterized by abnormally dilated intracranial capillaries, result in increased susceptibility to stroke. KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) have been identified as causes of CCMs in which at least one of them is disrupted in most familial cases. Our goal is to identify potential biomarkers and genetic modifiers of CCMs, using a global comparative omics approach across several in vitro studies and multiple in vivo animal models. We hypothesize that through analysis of the CSC utilizing various omics, we can identify potential biomarkers and genetic modifiers, by systemically evaluating effectors and binding partners of the CSC as well as second layer interactors. Methods: We utilize a comparative omics approach analyzing multiple CCMs deficient animal models across nine independent studies at the genomic, transcriptomic, and proteomic levels to dissect alterations in various signaling cascades. Results: Our analysis revealed a large set of genes that were validated across multiple independent studies, suggesting an important role for these identified genes in CCM pathogenesis. Conclusion: This is currently one of the largest comparative omics analysis of CCM deficiencies across multiple models, allowing us to investigate global alterations among multiple signaling cascades involved in both angiogenic and non-angiogenic events and to also identify potential biomarker candidates of CCMs, which can be used for new therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

“…A comparative database in excel (Additional files 1 and 2) was set up for the nine total available CCM cohorts that were analyzed for our comparative omics studies [8,10,[19][20][21][22][23][24][25] (Fig. 1).…”

Section: Data Acquisitionmentioning

confidence: 99%

Comparative omics of CCM signaling complex (CSC)

et al. 2020

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“…We also screened screened drugs from the US Drug Collection of clinical trial stage compounds at 60 μM (MicroSource Discovery Systems). The concentration used for the latter two libraries was based on previous C. elegans screens performed in the 25-60 μM range (Kwok et al, 2006;Burns et al, 2010;Otten et al, 2018). This concentration range is used to overcome the poor bioaccumulation of exogenous compounds in C. elegans (Burns et al, 2010).…”

Section: Large Scale Chemical Screen In C Elegans Identifies 74 Unc-mentioning

confidence: 99%

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

Volpatti

Endo

Knox

et al. 2020

eLife

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Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in C. elegans which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca2+ release from wild type cells while promoting intracellular Ca2+ release in Ryr1 knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca2+ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.

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“…The research community has identified a number of different signaling pathways dysregulated following loss of the CCM genes: RhoA/ROCK [15][16][17][18], MEKK3-KLF2/4 [19][20][21], ICAP-1 and b1 integrin [22,23], DELTA-NOTCH [24], angiopoietin-2 [25], thrombomodulin and endothelial protein C receptor [26], reactive oxygen species (ROS) [27], autophagy [28], and endothelial-to-mesenchymal transition (EndMT) [29]. A nearly equal number of therapeutics have also been proposed or tested in CCM models: statins [15], fasudil [30], TGF-b inhibitors [29], sulindac [31], tempol [32], vitamin D3 [32], angiopoietin-2 neutralizing antibody [25], fluvastatin and zoledronate [33], indirubin-3'-monoxime [34], thrombospondin1 replacement [35], propranolol [36,37], ponatinib [38], BA1049 [39], and VEGFR2 inhibitor [40] . Several of these compounds arose from unbiased, highthroughput in vitro and in vivo screens of libraries containing thousands of compounds [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

“…A nearly equal number of therapeutics have also been proposed or tested in CCM models: statins [15], fasudil [30], TGF-b inhibitors [29], sulindac [31], tempol [32], vitamin D3 [32], angiopoietin-2 neutralizing antibody [25], fluvastatin and zoledronate [33], indirubin-3'-monoxime [34], thrombospondin1 replacement [35], propranolol [36,37], ponatinib [38], BA1049 [39], and VEGFR2 inhibitor [40] . Several of these compounds arose from unbiased, highthroughput in vitro and in vivo screens of libraries containing thousands of compounds [32][33][34]. However, despite the extensive mechanistic and therapeutic studies of CCM disease, a robust pharmacologic treatment for CCMs remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Novel hemorrhage models of cerebral cavernous malformations

Detter

Shenkar

Benavides

et al. 2020

Preprint

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Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies -fasudil, tempol, vitamin D3, and a combination of the three drugs failed to substantially reduce CCM formation when treatment was administered for five weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

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Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations

Cited by 36 publications

References 86 publications

Comparative omics of CCM signaling complex (CSC)

Comparative omics of CCM signaling complex (CSC)

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

Novel hemorrhage models of cerebral cavernous malformations

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