Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

Shukla, Rammohan; Henkel, Nicholas; Alganem, Khaled; Hamoud, Abdul‐rizaq; Reigle, James; Alnafisah, Rawan; Eby, Hunter M.; Imami, Ali Sajid; Creeden, Justin; Miruzzi, Scott A.; Meller, Jarosław; McCullumsmith, Robert E.

doi:10.1101/2020.04.24.060392

Cited by 5 publications

(4 citation statements)

References 136 publications

(125 reference statements)

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“…Any of these changes individually, or multiple multimodal changes across levels, may result in alterations in cellular function that produce a phenotype. RNA sequencing has been used to analyze the pathogenesis of many diseases and shows great potential for the identification of therapeutically significant pathways (25). Further, kinases play a critical role in signal transduction, control most cellular functions, and are abnormally phosphorylated in a wide range of diseases, making kinome array profiling (i.e., functional proteomics) an intriguing avenue for the identification of kinases as potential druggable targets (26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

Nguyen,

Curtis,

Imami

et al. 2023

Preprint

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Neurodevelopmental disorders (NDDs) are a category of pervasive disorders of the developing nervous system with few or no recognized biomarkers. A significant portion of the risk for NDDs, including attention deficit hyperactivity disorder (ADHD), is contributed by the environment, and exposure to pyrethroid pesticides during pregnancy has been identified as a potential risk factor for NDD in the unborn child. We recently showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice causes male-biased changes to ADHD- and NDD-relevant behaviors as well as the striatal dopamine system. Here, we used a multiomics approach to determine the broadest possible set of pharmacologically relevant changes in the mouse brain caused by developmental pyrethroid exposure (DPE). Using a litter-based, split-sample design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood, euthanized them, and pulverized and divided whole brain samples for split-sample transcriptomics, kinomics and multiomics integration. Transcriptome analysis revealed alterations to multiple canonical clock genes, and kinome analysis revealed changes in the activity of multiple kinases involved in synaptic plasticity. Multiomics integration revealed a dysregulated protein-protein interaction network containing primary clusters for mitogen-activated protein (MAP) kinase cascades, synaptic function, and the regulation of apoptosis. These results demonstrate that DPE causes a multi-modal biophenotype in the brain relevant to ADHD and identifies new potential avenues for therapeutics.

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Section: Introductionmentioning

confidence: 99%

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

Nguyen,

Curtis,

Imami

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, the list of therapeutically accessible likely GoF genes will expand and may provide important context when considering which treatment candidate to prioritize in vitro when investigating novel causal variants. Furthermore, recent work from our laboratory and others has leveraged published RNA sequencing data to identify downregulators of gene targets (Shukla et al, 2020; Wang et al, 2020). A similar approach in this context would be complementary and may lead to rapid successful drug repurposing capable of providing direct benefit to patients.…”

Section: Discussionmentioning

confidence: 99%

Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases

Ressler

Goldstein

2022

Molec Gen & Gen Med

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Purpose Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well‐studied genes, the direct effects of pathogenic variants are well documented as loss‐of‐function, gain‐of‐function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss‐ or gain‐of‐function would directly inform drug development strategies. Methods We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss‐of‐function. Results We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss‐ or gain‐of‐function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain‐of‐function or hypermorphic pathogenic variants. Conclusions We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.

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“…Thus, the list of therapeutically accessible likely GoF genes will expand and may provide important context when considering which treatment candidate to prioritize in vitro when investigating novel causal variants. Further, recent work from our lab and others has leveraged published RNA sequencing data to identify downregulators of gene targets 28,29 . A similar approach in this context would be complementary and may lead to rapid successful drug repurposing capable of providing direct benefit to patients.…”

Section: Discussionmentioning

confidence: 99%

Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases

Ressler

Goldstein²

2020

Preprint

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Purpose Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well-studied genes, the direct effects of pathogenic variants are well documented as loss of function, gain of function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss or gain of function would directly inform drug development strategies. Methods We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss of function. Results We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss or gain of function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain of function or hypermorphic pathogenic variants. Conclusions We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.

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Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

Cited by 5 publications

References 136 publications

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases

Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases

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