Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting approximately two to five of every 100,000 people worldwide. ALS is characterized by muscle weakness and paralysis as a result of motor neuron loss in the brain and spinal cord. Currently there is no cure for ALS. ALS patients are in urgent need of novel and effective treatments. Remarkably, most of ALS patients (>95%) have protein deposits in their degenerative neurons. These protein deposits always contain one protein called TDP-43. In the deposits, TDP-43 protein is abnormally folded (misfolding). Importantly, mutations in the gene encoding TDP-43 have also been found in some ALS patients. This evidence implies that TDP-43-targeting therapy to correct abnormally folded TDP-43 or to destroy the misfolded TDP-43 can be a promising therapy applicable to most ALS patients. This concept has been investigated in the last several years. However, the therapy targeting TDP-43 has not been realized yet primarily due to technical obstacles. The problem is that TDP-43 proteins are essential for our nervous system. Therefore, elimination of TDP-43 is not feasible. In the ALS patients, it is believed that there are two types of TDP-43. One is functional TDP-43 but the other is bad TDP-43 which is misfolded and thereby causes the disease. To develop an effective treatment targeting TDP-43, we need to discriminate good (functional) TDP-43 from bad TDP-43 (toxic misfolded TDP-43) and only bad TDP-43 needs to be eliminated, which is technically difficult.