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Article Dans Une Revue Journal of Crohn's and Colitis Année : 2022

Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases

Résumé

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.

Dates et versions

hal-03629318 , version 1 (04-04-2022)

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Flora Clément, Adrien Nougarède, Stéphanie Combe, Frédérique Kermarrec, Arindam Dey, et al.. Therapeutic siRNAs Targeting the JAK/STAT Signalling Pathway in Inflammatory Bowel Diseases. Journal of Crohn's and Colitis, 2022, 16 (2), pp.286-300. ⟨10.1093/ecco-jcc/jjab129⟩. ⟨hal-03629318⟩
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