TY - JOUR
T1 - Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin
AU - Tang, Qi
AU - Fakih, Hassan H.
AU - Zain UI Abideen, Mohammad
AU - Hildebrand, Samuel R.
AU - Afshari, Khashayar
AU - Gross, Katherine Y.
AU - Sousa, Jacquelyn
AU - Maebius, Allison S.
AU - Bartholdy, Christina
AU - Søgaard, Pia Pernille
AU - Jackerott, Malene
AU - Hariharan, Vignesh
AU - Summers, Ashley
AU - Fan, Xueli
AU - Okamura, Ken
AU - Monopoli, Kathryn R.
AU - Cooper, David A.
AU - Echeverria, Dimas
AU - Bramato, Brianna
AU - McHugh, Nicholas
AU - Furgal, Raymond C.
AU - Dresser, Karen
AU - Winter, Sarah J.
AU - Biscans, Annabelle
AU - Chuprin, Jane
AU - Haddadi, Nazgol Sadat
AU - Sherman, Shany
AU - Yıldız-Altay, Ümmügülsüm
AU - Rashighi, Mehdi
AU - Richmond, Jillian M.
AU - Bouix-Peter, Claire
AU - Blanchard, Carine
AU - Clauss, Adam
AU - Alterman, Julia F.
AU - Khvorova, Anastasia
AU - Harris, John E.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85175872823&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-42714-4
DO - 10.1038/s41467-023-42714-4
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C2 - 37925520
AN - SCOPUS:85175872823
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7099
ER -
