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 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

Cancer-driving mutations are enriched in genic regions intolerant to germline variation

“…The convergence of genes and genic sub-regions between these two disease areas suggest that similar biological processes play a fundamental role in these two groups of phenotypes. Indeed, cellular proliferation, chromatin remodeling, cell migration, and other cancer-relevant processes have been implicated in neurodevelopmental diseases (De Rubeis et al, 2014;Dhindsa et al, 2021;Feng et al, 2019;Kaplanis et al, 2020).…”

How can same-gene mutations promote both cancer and developmental disorders?

“…Network analysis suggested that RASopathy proteins participate in 33 pathways ( 111 ). Inclusion of drugs acting on chromatin modifiers, such as statins and histone deacetylase inhibitors, may have a better chance ( 71 ); however, contending with toxicity remains a challenge ( 129 ). Last, with the advent of the impact of artificial intelligence (AI), the question has been raised as to whether AI can offer a breakthrough in predicting risks and prognosis for neurodevelopmental disorders ( 130 ) and drug repurposing ( 131 ).…”

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain

“…Unfortunately, sulforaphane exhibits somewhat poor pharmacokinetics that limit its utility in humans ( 72 , 73 ). To screen for candidate alternatives to sulforaphane, we adapted a transcriptome-guided drug discovery scheme termed transcriptome reversal ( 74 , 75 ). Transcriptome reversal posits that if a dysregulated transcriptome drives a particular disease, then correcting the transcriptome back toward a normal state may be therapeutic.…”