P10 Janus kinase inhibitors to restore skin barrier function in a mouse model of Harlequin ichthyosis

Abstract

Abstract Introduction and aims The autosomal recessive congenital ichthyoses (ARCIs) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in transport of glucosylceramides from the lamellar body to the lipid lamellae. Several Janus kinase (JAK) inhibitors inhibiting the JAK-signal transducer and activator of transcription pathway are now licensed for atopic dermatitis. Previous work from our group in an HI in vitro model showed that tofacitinib, a pan-JAK inhibitor, had a restorative effect on the lipid barrier. Methods Further selective JAKis were tested in three dimensional skin equivalents using ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes to identify the most promising JAKi for use in an HI murine model (ABCA12tm1c: Het Cre+). JAKi-A (5 mg kg−1) and vehicle (10% dimethylsulfoxide in corn oil) were tested on male and female HI-inducible and wildtype mice (N = 4). All mice were initially treated with 4-OH-Tamoxifen to induce the HI phenotype and after 1 day JAKi-A was administered via oral gavage for 9 days. All mice were killed, and skin was collected and processed for haematoxylin and eosin, Nile Red, ABCA12, glucosylceramide and immune cell marker staining. Results JAKi-A had a positive effect on HI epidermal morphology, showing a significantly reduced epidermal thickness in treated HI mice compared with controls. JAKi-A also had a positive effect on the epidermal barrier, restoring neutral and polar lipids compared with vehicle-treated mice as observed using Nile Red and glucosylceramide staining. Further analysis on immune cell infiltrates is in progress. Conclusions These Results suggest that JAKi-A restores the skin barrier in vivo and may be a promising treatment for severe ichthyosis.