Targeting E-cadherin with a gapmer antisense oligonucleotide for treating X-linked ichthyosis

X-linked ichthyosis (XLI) is a keratinization disorder steroid sulfatase (STS) deficiency, with no effective treatment currently available. E-cadherin, an essential upstream regulator of keratinocyte differentiation, was markedly overexpressed in STS-deficient HaCaT cells, indicating its potential as a therapeutic target. Additionally, mutations introduced into the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratin 1 expression in keratinocytes. Treatment with miR-6766, which targets E-cadherin mRNA, downregulated early and terminal keratinocyte differentiation markers. Building on these results, a gapmer antisense oligonucleotide (gASO) with 2′-O-Methoxyethyl-modifications and phosphorothioate linkages was rationally designed to target the same E-cadherin RNA sequence recognized by miR-6766, offering enhanced potency and stability. gASO treatment resulted in stronger suppression of E-cadherin and keratin 1 expression than that of miR-6766, indicating superior inhibitory efficacy. gASO treatment at various concentrations (0, 25, 50, or 100 nM) in HaCaT cells led to a dose-dependent reduction in the expression of early (keratin 1 and keratin 10) and terminal (Transglutaminase1, involucrin, and loricrin) differentiation markers. A similar reduction in differentiation marker expression was observed under STS-deficient conditions. Therefore, this study aimed to evaluate the therapeutic potential of an E-cadherin-targeting gASO as a novel strategy to suppress abnormal keratinocyte differentiation in XLI. These findings suggest that a gASO targeting E-cadherin may serve as a promising therapeutic strategy for XLI by effectively suppressing keratinocyte differentiation.