726 Novel CYP26B1-selective inhibitor increases measures of epidermal barrier function in healthy, darier’s, and ichthyotic econstructed human epidermis

      The skin barrier, primarily by the stratum granulosum and stratum corneum of the epidermis, functions as our primary protection from dangerous pathogens, allergens, UV radiation, and mechanical injury, and plays a vital role in fluid and thermal regulation. This barrier is disrupted in several skin disorders ranging from atopic dermatitis, to rare genetic disorders, such as Darier’s disease and ichthyosis. Current treatment options do not adequately address patient needs, presenting significant efficacy or tolerability concerns. CYP26B1 is an isoform of cytochrome P450 family 26 enzymes which are responsible for the elimination of all-trans retinoic acid found in the skin. We have recently identified a novel substrate-based CYP26B1-selective inhibitor, DX314. Unexpectedly, we discovered evidence that DX314 substantially increases barrier function in reconstructed human epidermis (RHE) derived from healthy, Darier’s disease, and ichthyotic keratinocytes by measuring trans-epidermal electrical resistance (TEER), characterizing variable expression of barrier and tight junction proteins and mRNAs, and observing morphological changes. In contrast, we observed barrier disrupting effects when RHEs were treated with all-trans retinoic acid or non-selective CYP26 inhibitors. These preliminary results may lead to a novel therapeutic strategy for rescuing skin barrier function deficiencies, as well as elucidate the mechanisms underlying skin barrier function.