898 The proteasome inhibitor PTTC restores the lipid barrier in a harlequin ichthyosis in vitro skin model

Harlequin ichthyosis is a life threatening rare skin condition characterized by aberrant differentiation of the epidermis leading to severe barrier defect. It caused mutations in ABCA12 lipid transporter involved transport glucosylceramides from lamellar body lamellae. The current therapeutic approach consists topical emollients and oral administration retinoids causing side effects, so there an unmet need for new treatments. ubiquitin-proteasome pathway responsible maintaining protein homeostasis. 3,5-Ditert-butyl-4-hyroxyhydrocinnamate (PTTC) novel proteasome inhibitor which has been trialed humans rosacea andin vitro psoriasis. We hypothesized that PTTC could restore epidermal 3D organotypic (OT) models established using CRispR-Cas9 deletion ABCA12. After assessing concentrations/toxicity MTT assay, OTs generated KO WT keratinocytes were treated with at two concentrations (10 20 μM) compared negative controls vehicle only (n=4). stained H&E, Nile Red markers such as K10, K14, TGM1 involucrin. Epidermal thickness significantly decreased comparing all concentrations. However, 10 μM increase neutral polar translocation toward stratum corneum was seen, well normalisation expression K14 involucrin PTTC. This suggests positive effect restoring function OTs. These results are promising we considering further vivo studies.