By Diagnostics World Staff
October 26, 2018 | Scientists from the Icahn School of Medicine at Mount Sinai, Eli Lilly and Company, and Sema4 released results from a proof-of-concept study demonstrating that patient-derived cells offer a more effective approach for assessing drug response than conventional methods. These findings could pave the way for streamlined drug discovery, particularly for diseases such as schizophrenia that have seen little therapeutic innovation. The study was published this week in Nature Communications (DOI:https://doi.org/10.1038/s41467-018-06515-4).
Drug discovery for neuropsychiatric disorders such as schizophrenia is limited due to a lack of useful models for screening candidate treatments, the authors of the study write. Currently, all antipsychotic drugs approved by the U.S. Food and Drug Administration target the same dopamine receptor. Unfortunately, two-thirds of patients with schizophrenia have no response or only partial response to these treatments. New therapies are necessary, but without biologically relevant screening models there has been little progress.
In this new study, scientists theorized that more meaningful results could be generated from testing drug candidates on patient-derived cells, rather than on generic cell lines. They utilized cells isolated from 12 patients with schizophrenia and 12 healthy controls, generating induced pluripotent stem cells that were guided to become neural progenitor cells, the key cell type targeted for neuropsychiatric disorders.
Researchers prepared a series of assays from each individual’s cells, treated them with 135 different small molecules selected for their predicted or demonstrated interaction with schizophrenia-relevant biology, and analyzed gene activity. The same drugs were tested on commonly used cancer cell lines for comparison. Results showed that the patient-derived cells yielded more disease-relevant information than the generic cells. In some cases, certain drugs reversed the gene expression signatures associated with schizophrenia.
“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,” Kristen Brennand, Associate Professor of Neuroscience, Psychiatry, and Genetics and Genomic Sciences at Mount Sinai and senior author of the paper, said in a statement.
“This study nicely illustrates the importance of using an integrative genomics approach for improving drug discovery and, ultimately, patient care,” the Icahn Institute’s director for Data Science and Genomic Technology at Mount Sinai, Adam Margolin, wrote in a press release. “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.”
For this study, drug screening and transcriptome analysis were performed at Mount Sinai with compounds provided by Eli Lilly. Funding for the work came from Mount Sinai and Eli Lilly.