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 McHughRaymond 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*, John E. Harris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number7099
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023
Externally publishedYes

Funding

FundersFunder number
Bank of America Private Bank
Hartford Foundation Vitiligo
King Trust
UMass Chan Medical School
National Institutes of HealthS10 OD020012, R01 AR069114, K99 AR082987, S10 OD028576, R35 GM131839
Aldeyra Therapeutics

    Fingerprint

    Dive into the research topics of 'Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin'. Together they form a unique fingerprint.

    Cite this