Details

Autor(en) / Beteiligte

• Tang, Qi
• Sousa, Jacquelyn
• Echeverria, Dimas
• Fan, Xueli
• Hsueh, Ying-Chao
• Afshari, Khashayar
• MeHugh, Nicholas
• Cooper, David A.
• Vangjeli, Lorenc
• Monopoli, Kathryn
• Okamura, Ken
• Biscans, Annabelle
• Clauss, Adam
• Harris, John E.
• Khvorova, Anastasia

Titel

RNAi-based modulation of IFN-γ signaling in skin

Ist Teil von

• Molecular therapy, 2022-08, Vol.30 (8), p.2709-2721

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 IFN-γ receptor (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. ▪ Dysregulation of IFN-γ signaling has been found in several T cell-mediated autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. In this work, Khvorova, Harris, and colleagues developed a therapeutic siRNA that efficiently modulates the IFN-γ signaling to potentiate the treatment of autoimmune skin diseases.