Expression-based drug screening of neural progenitor cells from individuals with schizophrenia

Benjamin Readhead, Brigham J. Hartley, Brian J. Eastwood, David A. Collier, David Evans, Richard Farias, Ching He, Gabriel Hoffman, Pamela Sklar, Joel T. Dudley, Eric E. Schadt (), Radoslav Savić () and Kristen J. Brennand ()
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Benjamin Readhead: Icahn School of Medicine at Mount Sinai
Brigham J. Hartley: Icahn School of Medicine at Mount Sinai
Brian J. Eastwood: Erl Wood Manor
David A. Collier: Erl Wood Manor
David Evans: Erl Wood Manor
Richard Farias: Icahn School of Medicine at Mount Sinai
Ching He: Icahn School of Medicine at Mount Sinai
Gabriel Hoffman: Icahn School of Medicine at Mount Sinai
Pamela Sklar: Icahn School of Medicine at Mount Sinai
Joel T. Dudley: Icahn School of Medicine at Mount Sinai
Eric E. Schadt: Icahn School of Medicine at Mount Sinai
Radoslav Savić: Icahn School of Medicine at Mount Sinai
Kristen J. Brennand: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.

Date: 2018
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DOI: 10.1038/s41467-018-06515-4

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