Gapmer Antisense Oligonucleotide Targeting E-Cadherin Rescues Abnormal Keratinization in X-Linked Ichthyosis Models
10.4062/biomolther.2025.228
- Author:
Ji Heung KWAK
1
;
Tae-Uk KWON
;
Yeo-Jung KWON
;
Hyemin PARK
;
Yoon-ji KANG
;
Jeongeun SHIN
;
Young-Jin CHUN
Author Information
1. College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2026;34(1):213-224
- CountryRepublic of Korea
- Language:English
-
Abstract:
X-linked ichthyosis (XLI) is an inherited disorder of keratinization resulting from a deficiency of steroid sulfatase (STS), for which no effective therapy is currently available. E-cadherin, a key upstream regulator of keratinocyte differentiation, has been found to be markedly overexpressed in STS-deficient HaCaT cells, suggesting its potential as a therapeutic target in XLI. To investigate the functional role of E-cadherin and explore its therapeutic potential, we introduced mutations into the N-terminal region of Ecadherin and examined the resulting effects on keratinocyte differentiation. In addition, a microRNA (miR-6766) and a rationally designed gapmer antisense oligonucleotide (gASO) targeting the same E-cadherin mRNA sequence were employed to modulate E-cadherin expression in HaCaT cells. Mutations within the N-terminal region of E-cadherin significantly reduced keratin 1 expression, underscoring the critical role of this domain in regulating keratinocyte differentiation. Treatment with miR-6766 led todownregulation of both early and terminal differentiation markers. Building on this, the gASO modified with 2′-O-methoxyethyl andphosphorothioate linkages exhibited enhanced potency and stability, resulting in stronger suppression of E-cadherin and keratin 1 expression compared with miR-6766 (maintained 37.7% greater inhibition of E-cadherin at 96 h and 35.7% greater inhibition of keratin 1 at 96 h). Furthermore, gASO treatment induced a concentration-dependent reduction in early (keratin 1 and keratin 10) and terminal (transglutaminase 1, involucrin, and loricrin) differentiation markers. These findings demonstrate that an E-cadherin– targeting gASO effectively suppresses abnormal keratinocyte differentiation and may serve as a promising therapeutic strategy for X-linked ichthyosis.
