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 Hildebrand, Khashayar Afshari, Katherine Y. Gross, Jacquelyn Sousa, Allison Maebius, Christina Bartholdy, Pia Pernille Søgaard, Malene Jackerott, Vignesh Hariharan, Ashley Summers, Xueli Fan, Ken Okamura, Kathryn Monopoli, David Cooper, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, Raymond 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
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.