Antisense oligonucleotide depletion of CCDC146 is a broad-spectrum therapeutic strategy for ALS.

Abstract

Amyotrophic lateral sclerosis (ALS) is a heritable and incurable disease defined by the degeneration of motor neurons (MNs), yet the genetics of ALS remain partially understood. Using a genomic deep learning-powered whole-genome analysis of 6,715 ALS patients, we identify four rare noncoding variants associated with patient survival, including chr7:76,009,472:C>T which is linked to a 70.6% reduction in survival. Genetic editing of this variant into iPSC-derived MNs increases CCDC146 expression and exacerbates ALS-specific phenotypes including TDP-43 mislocalization. We reveal that CCDC146 was located within the basal body of primary cilia in human MNs, and that cilia structure and function is impaired by CCDC146 overexpression but is restored by its depletion. Suppressing CCDC146 using an antisense oligonucleotide (ASO) completely rescues ALS-specific survival defects in neurons derived from both sporadic and familial patients, and it extends survival and reverses TDP-43 pathology in an aggressive ALS mouse model. Taken together, CCDC146 is a new modifier of ALS survival that acts via the primary cilia of MNs. ASO targeting of CCDC146 is a potential therapeutic approach for both sporadic and genetic forms of ALS, particularly because congenital absence of CCDC146 is well tolerated.