Protein Tyrosine Phosphatase Conjugated with a Novel Transdermal Delivery Peptide, AP-rPTP Alleviates both Atopic Dermatitis-like and Psoriasis-like Dermatitis

Publication date: Available online 26 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Won-Ju Kim, Ja-Hyun Koo, Hyun-Jung Cho, Jae-Ung Lee, Ji Yun Kim, Hong-Gyun Lee, Sohee Lee, Jong Hoon Kim, Mi Seon Oh, Minah Suh, Eui-Cheol Shin, Joo Yeon Ko, Myung Hyun Sohn, Je-Min Choi
BackgroundAtopic dermatitis and psoriasis are the two most common chronic inflammatory skin diseases. There is an unmet medical need to overcome limitations for transcutaneous drug development posed by the skin barrier.ObjectiveWe aimed to identify a novel transdermal delivery peptide and to develop a transcutaneously applicable immunomodulatory protein for treating atopic dermatitis and psoriasis.MethodsWe identified and generated reporter proteins conjugated to AP, a novel transdermal delivery peptide of human origin, and analyzed the intracellular delivery efficiency of these proteins in mouse and human skin cells and tissues using multi-photon confocal microscopy. We also generated a recombinant therapeutic protein, AP-rPTP, consisting of the phosphatase domain of T cell protein tyrosine phosphatase (TC-PTP) conjugated to AP. The immunomodulatory function of AP-rPTP was confirmed in splenocytes upon cytokine stimulation and TcR stimulation. Finally, we confirmed the in vivo efficacy of AP-rPTP transdermal delivery in OXA-induced contact hypersensitivity, OVA-induced atopic dermatitis-like, and imiquimod-induced psoriasis-like skin inflammation models.ResultsAP-conjugated reporter proteins exhibited significant intracellular transduction efficacy in keratinocytes, fibroblasts, and immune cells. In addition, transcutaneous administration of AP-dTomato resulted in showed significant localization into the dermis and epidermis in both mouse and human skin. AP-rPTP inhibited pSTAT1, pSTAT3, and pSTAT6 in splenocytes and also regulated T cell activation and proliferation. Transcutaneous administration of AP-rPTP via the paper-patch technique significantly ameliorated skin tissue thickening, inflammation, and cytokine expression in both atopic dermatitis-like and psoriasis-like dermatitis models.ConclusionWe identified a 9-amino acid-long novel transdermal delivery peptide, AP, and demonstrated its feasibility for transcutaneous biologic drug development. Moreover, AP-rPTP is a novel immunomodulatory drug candidate for human dermatitis.

Teaser

A novel therapeutic version of protein tyrosine phosphatase with a biochemical enhancer penetrated the skin tissue barrier and ameliorated the inflammatory response in AD-like and psoriasis- like skin diseases.


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