Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
Authors
Qi Tang, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Hassan H. Fakih, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Mohammad Zain Ui Abideen, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Samuel R. Hildebrand, RNA Therapeutics Institute, 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.
Katherine Y. Gross, RNA Therapeutics Institute, 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.
Allison S. Maebius, Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Christina Bartholdy, LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
Pia Pernille Søgaard, LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
Malene Jackerott, LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
Vignesh Hariharan, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Ashley Summers, 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.
Ken Okamura, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Kathryn R. Monopoli, 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.
Dimas Echeverria, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Brianna Bramato, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Nicholas McHugh, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Raymond C. Furgal, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Karen Dresser, Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Sarah J. Winter, RNA Therapeutics Institute, 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.
Jane Chuprin, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Nazgol-Sadat Haddadi, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Shany Sherman, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Ümmügülsüm Yıldız-Altay, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Mehdi Rashighi, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Jillian M. Richmond, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Claire Bouix-Peter, Aldena Therapeutics, London, E1 6RA, UK.
Carine Blanchard, Aldena Therapeutics, London, E1 6RA, UK.
Publication Title
Nature communications
Abstract
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.
DOI
10.1038/s41467-023-42714-4
Publication Date
11-4-2023
Recommended Citation
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; and Blanchard, Carine, "Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin" (2023). Internal Medicine. 295.
https://scholar.bridgeporthospital.org/internal_medicine/295
Identifier
37925520 (pubmed); PMC10625637 (pmc); 10.1038/s41467-023-42714-4 (doi); 10.1038/s41467-023-42714-4 (pii)
