Our results demonstrate that lowering TDP-43 levels using ENA-modified gapmer ASOs leads to the sustained improvement of disease phenotypes and TDP-43 pathology in vivo, indicating the therapeutic potential of the TDP-43-lowering approach for treatment of the TDP-43-associated diseases (TDP-43 proteinopathies), including ALS/FTD. The gene discussed is TARDBP; the disease is frontotemporal dementia.