RNAi-based modulation of IFN-γ signaling in skin

Qi Tang, 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.
Jacquelyn Sousa, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Dimas Echeverria, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Xueli Fan, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Ying-Chao Hsueh, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Immunology and Microbiology Program, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Khashayar Afshari, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Nicholas MeHugh, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
David A. Cooper, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Lorenc Vangjeli, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Kathryn Monopoli, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
Ken Okamura, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Annabelle Biscans, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Adam Clauss, LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
John E. Harris, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: john.harris@umassmed.edu.
Anastasia Khvorova, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: anastasia.khvorova@umassmed.edu.

Document Type

Article

Publication Title

Molecular therapy : the journal of the American Society of Gene Therapy

Abstract

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.

First Page

2709

Last Page

2721

DOI

10.1016/j.ymthe.2022.04.019

Publication Date

8-3-2022

Identifier

35477658 (pubmed); PMC9372319 (pmc); 10.1016/j.ymthe.2022.04.019 (doi); S1525-0016(22)00249-0 (pii)

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