Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are devastating diseases with no effective treatments. This study aims to develop a long-acting ENA-modified nucleic acid drug to address a core problem in these diseases: the abnormal behavior of the TDP-43 protein. By targeting the phase separation and mislocalization of TDP-43, we can correct its toxic gain and loss of function. Our goal is to establish an innovative therapeutic strategy for ALS/FTLD through validation in cultured cells, mouse models, and neurons derived from patient iPS cells.