Background

Amyotrophic lateral sclerosis (ALS) is a progressive and intractable motor neuron disease marked by systemic muscle atrophy and weakness. In over 95% of sporadic and familial ALS cases, cytoplasmic aggregates of the 43-kDa TAR DNA-binding protein (TDP-43) are found in neurons. Mutations in the TARDBP gene, which encodes TDP-43, further highlight its central role in ALS pathogenesis. However, there are currently no efficient therapies that directly target TDP-43. While nucleic acid-based disease-modifying therapies (DMTs) are advancing for familial ALS, developing DMTs for sporadic ALS ‑ the majority of cases ‑ remains profoundly challenging. This is partly due to the essential and tightly regulated functions of TDP-43, an RNA-binding protein involved in RNA splicing. Its suppression causes loss of function,