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

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.