Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases. (21st July 2021)

• Record Type: Journal Article
• Authors: Clément, Flora; Nougarède, Adrien; Combe, Stéphanie; Kermarrec, Frédérique; Dey, Arindam K; Obeid, Patricia; Millet, Arnaud; Navarro, Fabrice P; Marche, Patrice N; Sulpice, Eric; Gidrol, Xavier
• Is Part Of: Journal of Crohn's and colitis. Volume 16:Number 2(2022)
• Page Start: 286
• Page End: 300
• Publication Date: 2021-07-21
• Subjects: Therapeutic siRNA -- JAK inhibitors -- inflammatory bowel diseases; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjab129
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: Inflammatory bowel diseases are highly debilitating conditions that require constant monitoring and life-long medication. Current treatments are focused on systemic administration of immunomodulatory drugs, but they have a broad range of undesirable side-effects. RNA interference is a highly specific endogenous mechanism that regulates the expression of the gene at the transcript level, which can be repurposed using exogenous short interfering RNA [siRNA] to repress expression of the target gene. While siRNA therapeutics can offer an alternative to existing therapies, with a high specificity critical for chronically administrated drugs, evidence of their potency compared to chemical kinase inhibitors used in clinics is still lacking in alleviating an adverse inflammatory response. Methods: We provide a framework to select highly specific siRNA, with a focus on two kinases strongly involved in pro-inflammatory diseases, namely JAK1 and JAK3. Using western-blot, real-time quantitative PCR and large-scale analysis, we assessed the specificity profile of these siRNA drugs and compared their efficacy to the most recent and promising kinase inhibitors for Janus kinases [Jakinibs], tofacitinib and filgotinib. Results: siRNA drugs can reach higher efficiency and selectivity at lower doses [5 pM vs 1 µM] than Jakinibs. Moreover, JAK silencing lasted up to 11 days, even with 6 h pulse transfection. Conclusions: The siRNA-based drugs developed hold the potential to develop more potent therapeutics for chronic inflammatory diseases. Graphical Abstract: