A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders

Ryan S Dhindsa; Anthony W Zoghbi; Daniel K Krizay; Chirag Vasavda; David B Goldstein

doi:10.1002/ana.25950

A Transcriptome-Based Drug Discovery Paradigm for Neurodevelopmental Disorders

Ann Neurol. 2021 Feb;89(2):199-211. doi: 10.1002/ana.25950. Epub 2020 Nov 18.

Authors

Ryan S Dhindsa^{1

2}, Anthony W Zoghbi^{1

3}, Daniel K Krizay^{1

4}, Chirag Vasavda⁵, David B Goldstein^{1

4}

Affiliations

¹ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Psychiatry, Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA.
⁴ Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anticonvulsants / pharmacology
Antidepressive Agents / pharmacology
Antipsychotic Agents / pharmacology
Carbamazepine / pharmacology
Computer Simulation
Drug Discovery
Epirizole / pharmacology
Gene Expression Profiling
Gene Expression Regulation / genetics*
Humans
Induced Pluripotent Stem Cells
MCF-7 Cells
Mice
Naloxone / pharmacology
Narcotic Antagonists / pharmacology
Neural Stem Cells / drug effects*
Neural Stem Cells / metabolism
Neurodevelopmental Disorders / drug therapy*
Neurodevelopmental Disorders / genetics
Neurons / drug effects*
Neurons / metabolism
PC-3 Cells
Perphenazine / pharmacology
Primary Cell Culture
RNA-Seq
Risperidone / pharmacology
Single-Cell Analysis
Transcriptome / drug effects*
Trazodone / pharmacology
Trimipramine / pharmacology

Substances

Anti-Inflammatory Agents, Non-Steroidal
Anticonvulsants
Antidepressive Agents
Antipsychotic Agents
Narcotic Antagonists
Carbamazepine
Naloxone
Epirizole
Trimipramine
Perphenazine
Risperidone
Trazodone

Abstract

MeSH terms

Substances

Grants and funding