ASOs have recently emerged as a powerful therapeutic option for disease intervention, including those caused by trinucleotide repeat expansions.10, 39, 40, 41, 42 Here we show that a non-coding CTG trinucleotide repeat expansion in TCF4 (CTG18.1) confers greater than 76-fold risk for FECD in a large white British and Czech cohort. We demonstrate that primary CECs derived from FECD-affected subjects display the predicted hallmarks of primary and downstream repeat-expansion-associated pathology, and subsequently show that these changes are reversed by an ASO treatment specifically targeted at the CTG18.1 trinucleotide repeat expansion. An ASO-based treatment could therefore offer an innovative therapeutic approach that could benefit a substantial number of individuals affected by this common and sight-threatening condition.43