Studies now support a central role for disruptions in the nuclear transport machinery, including nuclear pore complexes (NPC) and nucleocytoplasmic transport (NCT) as being causative or contributing to C9orf72 FTD/ALS pathogenesis. Alterations to the NPC are the critical initiating event that begins the cascade of cellular downstream injury, including loss of nuclear TDP-43 function and neuronal death. Altered NCT may be a primary and early pathological feature of TDP-43-associated neurodegenerative disease. The cause of this upstream pathogenic process is the aberrant neuronal nuclear localization of CHMP7 which initiates the injury to the NPC. Inhibition of CHMP7, by antisense oligonucleotides (ASO), mitigates this upstream injury and normalizes NCT and TDP-43 function. As defects in NPC and TDP-43 are common in C9orf72 FTD/ALS, prevention of this injury has high therapeutic potential. We have developed several highly specific and potent CHMP7 ASOs that appear to mitigate this sporadic and familial ALS pathophysiological cascade. The objective of this proposal is to demonstrate that a specific CHMP7 ASO candidate can effectively lower CHMP7 protein in individual C9orf72 FTD/ALS and sporadic FTD patient iPSC lines and demonstrate that this not only repairs the NPC, but alleviates downstream TDP-43 loss of function, is non-toxic, has no adverse effects on cellular pathways that rely on ESCRT-III machinery, and prevents neuronal sensitivity to stressors. The goals of this proposal are to 1. Use a panel of well-characterized iPSC lines to validate the specificity and efficacy of human CHMP7 ASOs in reducing CHMP7 and the implications for disease pathophysiology and overall cellular health and eventually 2. Determine the safety of chronic administration and knockdown of CHMP7 in humanized CHMP-7 rodents employing specific CHMP7 ASOs. Collectively, these studies will define the efficacy of CHMP7 and provide the necessary data to move this ASO toward human trial in C9orf72 FTD patients.