A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

Prashant K Srivastava; Jonathan van Eyll; Patrice Godard; Manuela Mazzuferi; Andree Delahaye-Duriez; Juliette Van Steenwinckel; Pierre Gressens; Benedicte Danis; Catherine Vandenplas; Patrik Foerch; Karine Leclercq; Georges Mairet-Coello; Alvaro Cardenas; Frederic Vanclef; Liisi Laaniste; Isabelle Niespodziany; James Keaney; Julien Gasser; Gaelle Gillet; Kirill Shkura; Seon-Ah Chong; Jacques Behmoaras; Irena Kadiu; Enrico Petretto; Rafal M Kaminski; Michael R Johnson

doi:10.1038/s41467-018-06008-4

A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

Prashant K Srivastava, Jonathan van Eyll, Patrice Godard, Manuela Mazzuferi, Andree Delahaye-Duriez, Juliette Van Steenwinckel, Pierre Gressens, Benedicte Danis, Catherine Vandenplas, Patrik Foerch, Karine Leclercq, Georges Mairet-Coello, Alvaro Cardenas, Frederic Vanclef, Liisi Laaniste, Isabelle Niespodziany, James Keaney, Julien Gasser, Gaelle Gillet, Kirill ShkuraSeon-Ah Chong, Jacques Behmoaras, Irena Kadiu, Enrico Petretto, Rafal M Kaminski, Michael R Johnson

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Abstract

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.

Original language	English
Pages (from-to)	3561
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06008-4
Publication status	Published - 3 Sept 2018

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A systems-level framework_SRIVASTAVA_Publishedonline3September2018_GOLD VoR (CC BY)Final published version, 1.37 MBLicence: CC BY

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Srivastava, P. K., van Eyll, J., Godard, P., Mazzuferi, M., Delahaye-Duriez, A., Steenwinckel, J. V., Gressens, P., Danis, B., Vandenplas, C., Foerch, P., Leclercq, K., Mairet-Coello, G., Cardenas, A., Vanclef, F., Laaniste, L., Niespodziany, I., Keaney, J., Gasser, J., Gillet, G., ... Johnson, M. R. (2018). A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nature Communications, 9(1), 3561. https://doi.org/10.1038/s41467-018-06008-4

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abstract = "The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ({"}Causal Reasoning Analytical Framework for Target discovery{"}-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.",

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Srivastava, PK, van Eyll, J, Godard, P, Mazzuferi, M, Delahaye-Duriez, A, Steenwinckel, JV, Gressens, P, Danis, B, Vandenplas, C, Foerch, P, Leclercq, K, Mairet-Coello, G, Cardenas, A, Vanclef, F, Laaniste, L, Niespodziany, I, Keaney, J, Gasser, J, Gillet, G, Shkura, K, Chong, S-A, Behmoaras, J, Kadiu, I, Petretto, E, Kaminski, RM & Johnson, MR 2018, 'A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target', Nature Communications, vol. 9, no. 1, pp. 3561. https://doi.org/10.1038/s41467-018-06008-4

TY - JOUR

T1 - A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

AU - Srivastava, Prashant K

AU - van Eyll, Jonathan

AU - Godard, Patrice

AU - Mazzuferi, Manuela

AU - Delahaye-Duriez, Andree

AU - Steenwinckel, Juliette Van

AU - Gressens, Pierre

AU - Danis, Benedicte

AU - Vandenplas, Catherine

AU - Foerch, Patrik

AU - Leclercq, Karine

AU - Mairet-Coello, Georges

AU - Cardenas, Alvaro

AU - Vanclef, Frederic

AU - Laaniste, Liisi

AU - Niespodziany, Isabelle

AU - Keaney, James

AU - Gasser, Julien

AU - Gillet, Gaelle

AU - Shkura, Kirill

AU - Chong, Seon-Ah

AU - Behmoaras, Jacques

AU - Kadiu, Irena

AU - Petretto, Enrico

AU - Kaminski, Rafal M

AU - Johnson, Michael R

PY - 2018/9/3

Y1 - 2018/9/3

N2 - The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.

AB - The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning ("Causal Reasoning Analytical Framework for Target discovery"-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.

U2 - 10.1038/s41467-018-06008-4

DO - 10.1038/s41467-018-06008-4

M3 - Article

C2 - 30177815

SN - 2041-1723

VL - 9

SP - 3561

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

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