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Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFNreceptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases. Published by Elsevier Inc.


Qi Tang, Jacquelyn Sousa, Dimas Echeverria, Xueli Fan, Ying-Chao Hsueh, Khashayar Afshari, Nicholas MeHugh, David A Cooper, Lorenc Vangjeli, Kathryn Monopoli, Ken Okamura, Annabelle Biscans, Adam Clauss, John E Harris, Anastasia Khvorova. RNAi-based modulation of IFN-γ signaling in skin. Molecular therapy : the journal of the American Society of Gene Therapy. 2022 Aug 03;30(8):2709-2721

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PMID: 35477658

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