Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders

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 called "transcriptome reversal" for these disorders. This approach, originally developed for cancer, attempts to identify compounds that reverse gene-expression signatures associated with disease states.

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

“…Thus, we leveraged the transcriptomic profiles of TDP-43 MNs to search for compounds predicted to correct gene expression using the CMap database. This drug discovery strategy was previously applied to several human conditions including aortic valve disease, 103,104 non-alcoholic steatohepatitis, 105 epilepsy, [106][107][108] schizophrenia, 109 neurodevelopmental disorders, 41 and FTD, 110 yet remains largely unexplored in the ALS field.…”

“…As dysregulation of gene expression can have broad downstream consequences, determining the transcriptome alterations that arise in ALS can inform the development of transcriptome-correcting therapies. This drug discovery paradigm, known as "transcriptome reversal", 41 could give rise to therapies able to normalize several disease pathways simultaneously.…”

“…30.578100 doi: bioRxiv preprint therapies. This drug discovery paradigm, known as "transcriptome reversal", 41 could give rise to therapies able to normalize several disease pathways simultaneously.…”