Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
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Published:2023-11-04
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Tang QiORCID, Fakih Hassan H.ORCID, Zain UI Abideen Mohammad, Hildebrand Samuel R., Afshari Khashayar, Gross Katherine Y., Sousa Jacquelyn, Maebius Allison S., Bartholdy Christina, Søgaard Pia PernilleORCID, Jackerott MaleneORCID, Hariharan VigneshORCID, Summers AshleyORCID, Fan Xueli, Okamura KenORCID, Monopoli Kathryn R.ORCID, Cooper David A.ORCID, Echeverria Dimas, Bramato Brianna, McHugh NicholasORCID, Furgal Raymond C.ORCID, Dresser KarenORCID, Winter Sarah J., Biscans AnnabelleORCID, Chuprin JaneORCID, Haddadi Nazgol-SadatORCID, Sherman Shany, Yıldız-Altay ÜmmügülsümORCID, Rashighi Mehdi, Richmond Jillian M., Bouix-Peter Claire, Blanchard CarineORCID, Clauss AdamORCID, Alterman Julia F.ORCID, Khvorova AnastasiaORCID, Harris John E.ORCID
Abstract
AbstractInhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences U.S. Department of Health & Human Services | NIH | NIH Office of the Director
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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