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Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.
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; Yildiz-Altay, Ümmügülsüm; Rashighi, Mehdi; Richmond, Jillian M; Bouix-Peter, Claire; Blanchard, Carine; Clauss, Adam; Alterman, Julia F; Khvorova, Anastasia; Harris, John E.
Afiliación
  • Tang Q; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Fakih HH; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Zain Ui Abideen M; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Hildebrand SR; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Afshari K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Gross KY; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Sousa J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Maebius AS; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Bartholdy C; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Søgaard PP; LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
  • Jackerott M; LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
  • Hariharan V; LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
  • Summers A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Fan X; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Okamura K; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Monopoli KR; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Cooper DA; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Echeverria D; Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA, 01609, USA.
  • Bramato B; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • McHugh N; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Furgal RC; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Dresser K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Winter SJ; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Biscans A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Chuprin J; Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Haddadi NS; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Sherman S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Yildiz-Altay Ü; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Rashighi M; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Richmond JM; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Bouix-Peter C; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Blanchard C; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Clauss A; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • Alterman JF; Aldena Therapeutics, London, E1 6RA, UK.
  • Khvorova A; Aldena Therapeutics, London, E1 6RA, UK.
  • Harris JE; LEO Pharma A/S, Industriparken 55, 2750, Ballerup, Denmark.
Nat Commun ; 14(1): 7099, 2023 11 04.
Article en En | MEDLINE | ID: mdl-37925520
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vitíligo / Inhibidores de las Cinasas Janus Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vitíligo / Inhibidores de las Cinasas Janus Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos