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

Qi Tang, Hassan H. Fakih, Mohammad Zain UI Abideen, Samuel R. Hildebrand, Khashayar Afshari, Katherine Y. Gross, Jacquelyn Sousa, Allison S. Maebius, Christina Bartholdy, Pia Pernille Søgaard, Malene Jackerott, Vignesh Hariharan, Ashley Summers, Xueli Fan, Ken Okamura, Kathryn R. Monopoli, David A. Cooper, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, Raymond C. Furgal, Karen Dresser, Sarah J. Winter, Annabelle Biscans, Jane Chuprin, Nazgol-Sadat Haddadi, Shany Sherman, Ümmügülsüm Yıldız-Altay, Mehdi Rashighi, Jillian M. Richmond, Claire Bouix-Peter, Carine Blanchard, Adam Clauss, Julia F. Alterman (), Anastasia Khvorova () and John E. Harris ()
Additional contact information
Qi Tang: University of Massachusetts Chan Medical School
Hassan H. Fakih: University of Massachusetts Chan Medical School
Mohammad Zain UI Abideen: University of Massachusetts Chan Medical School
Samuel R. Hildebrand: University of Massachusetts Chan Medical School
Khashayar Afshari: University of Massachusetts Chan Medical School
Katherine Y. Gross: University of Massachusetts Chan Medical School
Jacquelyn Sousa: University of Massachusetts Chan Medical School
Allison S. Maebius: University of Massachusetts Chan Medical School
Christina Bartholdy: LEO Pharma A/S, Industriparken 55
Pia Pernille Søgaard: LEO Pharma A/S, Industriparken 55
Malene Jackerott: LEO Pharma A/S, Industriparken 55
Vignesh Hariharan: University of Massachusetts Chan Medical School
Ashley Summers: University of Massachusetts Chan Medical School
Xueli Fan: University of Massachusetts Chan Medical School
Ken Okamura: University of Massachusetts Chan Medical School
Kathryn R. Monopoli: University of Massachusetts Chan Medical School
David A. Cooper: University of Massachusetts Chan Medical School
Dimas Echeverria: University of Massachusetts Chan Medical School
Brianna Bramato: University of Massachusetts Chan Medical School
Nicholas McHugh: University of Massachusetts Chan Medical School
Raymond C. Furgal: University of Massachusetts Chan Medical School
Karen Dresser: University of Massachusetts Chan Medical School
Sarah J. Winter: University of Massachusetts Chan Medical School
Annabelle Biscans: University of Massachusetts Chan Medical School
Jane Chuprin: University of Massachusetts Chan Medical School
Nazgol-Sadat Haddadi: University of Massachusetts Chan Medical School
Shany Sherman: University of Massachusetts Chan Medical School
Ümmügülsüm Yıldız-Altay: University of Massachusetts Chan Medical School
Mehdi Rashighi: University of Massachusetts Chan Medical School
Jillian M. Richmond: University of Massachusetts Chan Medical School
Claire Bouix-Peter: Aldena Therapeutics
Carine Blanchard: Aldena Therapeutics
Adam Clauss: LEO Pharma A/S, Industriparken 55
Julia F. Alterman: University of Massachusetts Chan Medical School
Anastasia Khvorova: University of Massachusetts Chan Medical School
John E. Harris: University of Massachusetts Chan Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42714-4

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