RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Mol Ther. 2022 Aug 3;30(8):2709-2721. doi: 10.1016/j.ymthe.2022.04.019. Epub 2022 Apr 27.
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.
干扰素 (IFN)-γ 信号的异常激活在几种自身免疫性皮肤病中起着关键作用，包括红斑狼疮、斑秃、白癜风和扁平苔藓。在这里，我们鉴定了完全化学修饰的小干扰 RNA（siRNA），可沉默 IFN-γ 受体（IFNGR1）的配体结合链，从而调节 IFN-γ 信号。将这些 siRNA 与二十二酸（DCA）缀合可使它们有效地递送至注射部位附近的所有主要皮肤细胞类型，单次注射剂量可支持在小鼠中至少 1 个月的有效 IFNGR1 蛋白减少。在 IFN-γ 信号的离体模型中，DCA-siRNA 可有效抑制来自注射部位皮肤活检的 IFN-γ 诱导趋化因子 CXCL9 和 CXCL10 的诱导。我们的数据表明，可以对 DCA-siRNA 进行工程设计以在皮肤中实现功能性基因沉默，并为自身免疫性皮肤病的 siRNA 治疗开辟道路。
