Biology subjects

McManus, O.

Publications and source records attributed to McManus, O..

2 recordsLinked to original sources

bioRxiv2026

Excitatory Dysfunction and Phenotypic Rescue in a Human Neuronal Model of SCN2A-Related Disorders

SCN2A-related disorders result from pathogenic variants in the gene encoding for the voltage-gated sodium channel Nav1.2. Collectively, these disorders result in variable age of onset epilepsy, autism spectrum disorder, and epileptic encephalopathies. While the mechanisms of haploinsufficiency resulting in autism spectrum disorder have been explored in detail, few studies report the impact of pathogenic missense variants in human neurons. In this work, we combined conventional electrophysiology and high-throughput all-optical electrophysiology assays to analyze the SCN2A p.M1879T pathogenic variant associated with early-onset epilepsy and developmental delay. In both platforms, iPSC-derived excitatory neurons expressing the disease variant showed greater firing at higher stimuli compared to the isogenic control neurons (corrected by CRISPR/Cas9), as well as changes to action potential shape (steeper slope and larger amplitude) with evoked firing. We used machine learning techniques on the optical physiology dataset to classify the two genotypes, finding that sodium channel blocking anti-seizure drugs could restore an isogenic phenotype. This work demonstrates proof of sodium channel blocker efficacy in a human neuronal model of SCN2A-related epilepsy and highlights the power of leveraging high-throughput all-optical electrophysiology for testing drug efficacy.

neuroscience↗

bioRxiv2024

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the mTOR pathway genes TSC1 or TSC2. TSC can affect multiple organs including the brain, and most patients (75-90%) present with seizures during early childhood and intractable epilepsy throughout life. mTOR inhibitors, part of the current standard of care, lack the optimal characteristics to fully address patient phenotypes. Here, we report on the application of our all-optical electrophysiology platform for phenotypic screening in a human neuronal model of TSC. We used CRISPR/Cas9-isogenic TSC2-/- iPS cell lines to identify disease-associated changes to neuronal morphology, transcript expression and neuronal excitability. We established a robust multiparametric electrophysiological phenotype which we then validated in TSC patient-derived neurons. We used this phenotype to conduct a screen of [~]30,000 small molecule compounds in human iPS cell-derived neurons and identified chemical scaffolds that rescued the functional TSC disease parameters. Confirmed hits may act via different mechanisms than direct mTOR pathway inhibition. This strategy provides molecular starting points for therapeutic development in TSC and a framework for phenotype discovery and drug screening in other neurological disorders.

neuroscience↗