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Schizophrenia Drug Screening Improved Through Use of Patient-Derived Cells

NEW YORK (GenomeWeb) – Neural cells derived from human induced pluripotent stem cells can give insight into what drugs might treat schizophrenia, according to a new study.

Current drugs to treat people with schizophrenia are only effective in a portion of patients, as about two-thirds either don't respond to treatment or only partially respond. However, a lack of models has limited the ability to develop new therapies, the authors of the new study said.

As they reported in Nature Communications this week, researchers led by Kristen Brennand of the Ichan School of Medicine at Mount Sinai developed neural progenitor cells from 12 individuals with schizophrenia and from 12 controls and used those to test how a range of drugs influenced gene expression. A number of these drugs reversed a transcriptomic signature linked to schizophrenia. This suggested to the investigators that their approach could aid in drug discovery efforts.

"There is tremendous value in gene expression-based drug screening using patient-derived cells because it can generate results that are more reflective of disease biology," Brennand, an associate professor of neuroscience, psychiatry, and genetics and genomic sciences at Mount Sinai, said in a statement. Her co-authors include researchers from Eli Lilly and Sema4.

The researchers used an in silico approach to prioritize 135 small molecules out of a total 6,269 to be screened in the derived neural progenitor cells as well as in transformed cancer cell lines traditionally used in drug screening. Eli Lilly provided the drugs for screening.

These drugs were prioritized based on predicted or known interactions with schizophrenia-linked biology. Fifty-seven were selected based on their predicted ability to regulate the transcription of schizophrenia-linked genes, while 58 were known to target schizophrenia-linked genes themselves.

The researchers then gauged how exposure to these drugs affected gene expression within these cell types using Genometry's L1000 platform.

In particular, they examined how well the drugs could reverse a transcriptomic signature of schizophrenia. Of the 135 drugs tested, 52 ameliorated it, while 20 affected it in both control and schizophrenia-derived neural progenitor cells and 15 did so only in the schizophrenia-derived cells and 17 in control-derived cells only.

Overall, the researchers found that the neural progenitor cells derived from individuals with schizophrenia were more responsive to the drugs' effects than those derived from controls, but both were more responsive than the cancer cell lines. This, along with other findings, suggested to the researchers that that transcriptomic profiling in schizophrenia-relevant cells might better test drugs' effects.

More than a hundred of the drugs led to differential expression between neural progenitor cells derived from individuals with schizophrenia versus controls and 99 were linked to differential regulation of at least one schizophrenia gene set. Glipizide, they noted, had the strongest diagnosis-specific enrichment, while trimethobenzaminde had the strongest enrichment over a number of schizophrenia sets, the researchers noted.

Eighteen drugs both reversed the schizophrenia gene signature and differentially regulated schizophrenia gene sets in patient-derived neural progenitor cells.

The researchers particularly homed in on FMRP and its protein targets as they appeared to be affected by a number of the drugs tested in neural progenitor cell types generated from schizophrenia patients.

The research argued that an approach like theirs could improve the success rate of neuropsychiatric drug discovery.

"The results should be immediately applicable not only to drug discovery for schizophrenia but also more broadly to a wide range of diseases for which more biologically relevant screening models are long overdue," Adam Margolin, the director of the Icahn Institute for Data Science and Genomic Technology at Mount Sinai, said in a statement.

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