Background: Amyotrophic lateral sclerosis (ALS) remains a devastating neurodegenerative disease with minimal therapeutic options. With over 40 compounds having failed in randomised trials, riluzole remains the sole globally-approved treatment, offering a modest survival benefit. ALS pathogenesis involves complex mechanisms, including neuroinflammation, mitochondrial dysfunction, and, critically, TDP43-driven RNA dysregulation, which occurs in >95% of cases. We have applied DRUGseq, a novel high-throughput transcriptomics platform, adapted for drug discovery in iPSC-derived TDP-43 knock-out motor neurons. This produces compound-specific transcriptomic perturbation signatures in a disease-relevant model, enabling unprecedented transcriptome reversal approaches to drug discovery. We optimized the screen design: four technical repeats per compound at approximately two million reads/well ensures robust detection of differentially expressed genes whilst maintaining experimental feasibility. Validation studies demonstrate that DRUG-Seq successfully recapitulates known TDP43-mediated transcriptomic changes, including Stathmin2 and Unc13A alterations, with strong correlation to established RNA-sequencing technologies. Our platform has screened approximately 1,800 repurposed compounds, comprising CNS-penetrant drugs and FDA-approved compounds. Analysis is ongoing to identify compounds that reverse TDP43 loss-of-function. Furthermore, we have conducted a similar Full-Length DRUGseq screen to evaluate the effects of compounds on RNA splicing changes. This approach demonstrates transcriptome-guided drug repurposing for identifying novel single-agent or combination therapeutics in ALS.