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Abstract: There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3?) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase C?1-calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions.
Fuente: Science Advances, 2019, 5(5), eaau9093
Publisher: American Association for the Advancement of Science
Year of publication: 2019
No. of pages: 18
Publication type: Article
DOI: 10.1126/sciadv.aau9093
ISSN: 2375-2548
Publication Url: https://www.doi.org/10.1126/sciadv.aau9093
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LAGO, SANTIAGO G.
TOMASIK, JAKUB
REES, GEERTJE F. VAN
STEEB, HANNAH
COX, DAVID A.
RUSTOGI, NITIN
RAMSEY, JORDAN M.
BISHOP, JOSHUA A.
PETRYSHEN, TRACEY
HAGGARTY, STEPHEN J.
JAVIER VAZQUEZ BOURGON
PAPIOL, SERGI
PAULA SUAREZ PINILLA
BENEDICTO CRESPO FACORRO
BEVEREN, NICO J. VAN
BAHN, SABINE
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