In summary, we demonstrate proof-of-concept data that a targeted (CAG)7 ASO treatment reduces gain-of-function RNA toxicity induced by TCF4 CTG18.1 expansion, in a cellular and human genomic context. With the absence of FECD animal models, human ex vivo models are vital, both to provide a validation of the therapeutic approach for FECD and to continue the translation of ASO therapies into the clinic. ASO therapies are already in clinical trials for a variety of repeat expansion disorders including DM141 and Huntington disease (MIM: 143100), and additionally, intraocular ASO therapies are proposed for retinitis pigmentosa (RP [MIM: 268000]), RP associated with Usher syndrome (MIM: 608400), and Leber congenital amaurosis (MIM: 610142).49, 50, 51, 52 We propose that our proof-of-concept study provides evidence to translate this therapeutic approach to FECD given the accessibility of the diseased tissue and the relatively delayed onset of disease, which provides a window of opportunity to identify at risk individuals with TCF4 repeat expansions and prevent disease progression in pre-symptomatic individuals.