Multispecies-targeting siRNAs for the modulation of JAK1 in the skin

Qi Tang; Katherine Y. Gross; Hassan H. Fakih; Samuel O. Jackson; Mohammad Zain U.I. Abideen; Kathryn R. Monopoli; Carine Blanchard; Claire Bouix-Peter; Thibaud Portal; John E. Harris; Anastasia Khvorova; Julia F. Alterman

Molecular Therapy: Nucleic Acids (Mar 2024)

Multispecies-targeting siRNAs for the modulation of JAK1 in the skin

Qi Tang,
Katherine Y. Gross,
Hassan H. Fakih,
Samuel O. Jackson,
Mohammad Zain U.I. Abideen,
Kathryn R. Monopoli,
Carine Blanchard,
Claire Bouix-Peter,
Thibaud Portal,
John E. Harris,
Anastasia Khvorova,
Julia F. Alterman

Affiliations

Qi Tang: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Katherine Y. Gross: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Hassan H. Fakih: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Samuel O. Jackson: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Mohammad Zain U.I. Abideen: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Kathryn R. Monopoli: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609, USA
Carine Blanchard: Aldena Therapeutics, London E1 6RA, United Kingdom
Claire Bouix-Peter: Aldena Therapeutics, London E1 6RA, United Kingdom
Thibaud Portal: Aldena Therapeutics, London E1 6RA, United Kingdom
John E. Harris: Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author: John E. Harris, Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Anastasia Khvorova: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author: Anastasia Khvorova, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Julia F. Alterman: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author: Julia F. Alterman, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 35, no. 1
p. 102117

Abstract

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Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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