Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease, a severe neurodegenerative disease resulting in death within 2-5 years from diagnosis. Current therapies are non-specific, prolonging survival by less than three months in some patients, highlighting the urgent need for more targeted therapies. Mutations in Cu/Zn superoxide dismutase (SOD1) are a common cause of ALS, inducing disease through misfolded protein aggregates, leading to neuronal toxicity. Others have shown that SOD1 protein suppression could be therapeutic. We have developed splice-switching morpholino antisense oligonucleotides (PMOs) to induce the targeted removal of frame-shifting SOD1 exons to disrupt the reading frame, producing a premature termination codon that leads to nonsense mediated decay of the transcript. Following PMO transfection in iPSC-derived motor neurons from multiple SOD1 patient cell strains we observe up to 93% SOD1 protein suppression (P=0.001). Importantly, direct comparison of exon skipping PMOs with alternative SOD1 knockdown strategies in vitro, suggests that exon skipping PMOs are more effective at suppressing SOD1, and have a superior safety profile. Preliminary results of PMO evaluation in a transgenic SOD1G93A mouse model showed modest SOD1 exon skipping in some mice following administration of a low dose of PMO, with high dose treated mice currently being assessed. The levels of PMO-induced SOD1 knockdown in vitro, together with results by others showing the in vivo effects of SOD1 knockdown, strongly suggest this approach could have therapeutic potential for those with SOD1-ALS.