Developing a platform to improve the identification of therapies for Motor Neuron Disease (MND)

Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly fatal neurodegenerative disorder characterised by profound genetic and phenotypic heterogeneity. Despite decades of research, therapeutic development has yielded minimal clinical benefit, in part due to limitations in preclinical models and the absence of robust, translatable phenotypes suitable for industrial drug discovery. We address this gap by developing a reproducible platform to generate, phenotype, and validate induced pluripotent stem cell (iPSC)-derived motor neuron models for candidate gene triage.

First, an industrially compatible cellular handling pipeline was established to reduce motor neuron differentiation variability. A quantitative quality control framework combining immunocytochemistry, functional imaging, and genomic stability assessment enabled identification of key drivers of experimental variability and improved culture reproducibility. This provided a scalable foundation for downstream phenotypic interrogation.

Second, disease-relevant phenotypes were defined across genetically diverse MND models. Multiparametric phenotypic assays supported the existence of early, system-level pathological signatures shared across mutations. Of these, the stress, or unfolded protein response phenotype demonstrated robustness across different iPSC models and provided a novel readout for therapeutic assessment.

Third, an unbiased multi-omics framework was deployed to validate models and identify actionable pathways. Systems-level analysis revealed conserved MND signatures across mutations and highlighted pathways associated with oxidative phosphorylation and axonal health. Small-molecule modulation of selected pathways, independent of primary disease causative pathways, produced measurable rescue of robust cellular and omics MND phenotypes, providing proof of concept that omics-guided targeting of pathogenic-adjacent pathways can reverse disease relevant cellular dysfunction.

Together, this work delivers a reproducible platform for MND candidate gene triage and therapeutic validation in iPSC models, bridging the gap between human cellular disease modelling and practical drug discovery. We establish a framework for identifying therapeutically tractable pathways in complex neurodegenerative disease and provide a scalable strategy for future MND therapeutic development.