O09 Janus kinase inhibitors to restore skin barrier function in an in vivo model of harlequin ichthyosis

Abstract Introduction and aims Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis (ARCI) with aberrant lipid transport in the epidermis leading to a severe barrier defect. It is caused by variants in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. The aim of this study was to explore further the effect of Janus kinase inhibitors (JAKis) on the epidermal barrier in in vitro and in vivo models of HI. Methods Three-dimensional skin equivalents (3DSEs) were generated from human ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes and treated with the JAKi abrocitinib and upadacitinib (UPA) and bulk RNA sequencing (RNAseq) and lipidomics were performed. UPA was tested in an in vivo HI mouse model followed by haematoxylin and eosin, Nile red, ABCA12, glucosylceramide and immune cell staining. Results Bulk RNAseq on treated and control 3DSEs showed upregulation of genes involved in keratinocyte metabolism, differentiation and skin barrier function as well as downregulation in immune response genes post-JAKi. Lipidomic analysis showed upregulation of cholesterol sulfate and phosphatidylethanolamine post-JAKi. UPA was selected to test at a concentration of 5 mg kg−1 in 10% dimethyl sulfoxide/corn oil on adult male and female inducible Abca12flox/flox K14CreER and control mice (n = 4 per group, two repeats). One day after topical 4-OH-tamoxifen treatment, UPA or vehicle were administered via oral gavage for nine consecutive days before collecting back skin. The UPA-treated HI mice had significantly reduced epidermal thickness compared with controls. Nile red and glucosylceramide staining showed restoration of neutral and polar lipids and upper epidermal glucosylceramide in the UPA-treated mice compared with controls. A reduction in T cells and dendritic cells was also observed in the JAK1i-treated mice. Conclusions These results suggest that UPA restores the skin barrier in severe ichthyosis and may be a promising treatment for this group of patients.