Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Inhibition 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 selecti...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; p. 7099
Main Authors:	Tang, Qi, Fakih, Hassan H., Zain UI Abideen, Mohammad, Hildebrand, Samuel R., Afshari, Khashayar, Gross, Katherine Y., Sousa, Jacquelyn, Maebius, Allison S., Bartholdy, Christina, Søgaard, Pia Pernille, Jackerott, Malene, Hariharan, Vignesh, Summers, Ashley, Fan, Xueli, Okamura, Ken, Monopoli, Kathryn R., Cooper, David A., Echeverria, Dimas, Bramato, Brianna, McHugh, Nicholas, Furgal, Raymond C., Dresser, Karen, Winter, Sarah J., Biscans, Annabelle, Chuprin, Jane, Haddadi, Nazgol-Sadat, Sherman, Shany, Yıldız-Altay, Ümmügülsüm, Rashighi, Mehdi, Richmond, Jillian M., Bouix-Peter, Claire, Blanchard, Carine, Clauss, Adam, Alterman, Julia F., Khvorova, Anastasia, Harris, John E.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-11-2023 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/95 14/34 38/109 38/71 38/89 38/91 49/47 631/154/152 631/250/38 631/61/391/3932 64/110 64/60 64/86 692/4017 96/106 96/21 96/31 Animals Autoimmunity Autoimmunity - genetics CD8 antigen CD8-Positive T-Lymphocytes - metabolism Design Effectiveness Enzymes Gene silencing Humanities and Social Sciences Humans Janus kinase Janus Kinase 1 - genetics Janus Kinase 1 - metabolism Janus Kinase Inhibitors Kinases Lymphocytes Lymphocytes T Mice Modulation multidisciplinary RNA, Double-Stranded RNA, Small Interfering - genetics Safety Science Science (multidisciplinary) Selectivity siRNA Skin diseases Vitiligo Vitiligo - drug therapy Vitiligo - genetics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Inhibition 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. Therapeutic modulation of Janus kinase family enzymes is an established approach for inflammatory and autoimmune skin diseases. Here the authors rationally design small interfering RNAs to enable single Janus kinase targeting and test this new therapeutic approach in a skin disease model for maintaining efficacy and improving selectivity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-42714-4