Transcutaneous delivery of protein tyrosine phosphatase ameliorates inflammatory skin diseases

Transcutaneous delivery of therapeutic drugs has many advantages of topical treatment over the systemic administration for inflammatory skin diseases such as atopic dermatitis or psoriasis. However, the greatest challenge for transcutaneous drug delivery limits clinical applications due to the skin tissue barrier. Here, we identified a novel transcutaneous delivery peptide, AP, from human neuronal adhesion protein (Astrotactin 1) which could deliver a macromolecule such as a protein into skin tissue. AP-conjugated EGFP protein exhibited significantly higher intracellular transduction efficacy in HaCaT (keratinocyte), NIH3T3 (fibroblast) and Jurkat (T cell) cells compared with control proteins. In addition, AP-EGFP and –dTomato protein was efficiently localized into the dermis as well as epidermis in mouse skin tissue following transcutaneous administration. Next, we generated AP-rPTP protein, which is chimeric protein of AP and phosphatase domain of TC-PTP. AP-rPTP inhibited phosphorylation of STAT1, 3, 5 in mouse splenocytes and T cells and reduced cytokines production by activated splenocyets. To confirm its in vivo relevance, we transcutaneously applied it to dermatitis mouse models. Multiple skin patch administrations of AP-rPTP protein significantly ameliorated tissue inflammation in oxazolone-induced contact dermatitis and imiquimod-induced psoriasis mouse model. Our results collectively demonstrate that AP is a novel human derived transcutaneous delivery peptide and AP-rPTP protein could be a therapeutic biomolecule in inflammatory skin diseases such as allergic dermatitis and psoriasis.