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2021 - Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanised Mouse Model of Ulcerative Colitis

icon pl   Patchliner Publication in Journal of Crohn's and Colitis (2021)

Authors:
Unterweger A-L., Jensen M. Ø., Giordanetto F., Jogini V., Rüschher A., Seuß M., Winkelmann P., Koletzko L., Shaw D. E., Siebeck M., Gropp R., Beigel F., Aszodi A.

Journal:

Journal of Crohn's and Colitis (2021) doi:10.1093/ecco-jcc/jjab078


Abstract: 

Background and Aims: The potassium channel Kv1.3 is a potentially attractive therapeutic target in T cell-mediated inflammatory diseases, as the activity of antigen-activated T cells is selectively impeded by Kv1.3 inhibition. In this study, we examined Kv1.3 as a potential therapeutic intervention point for ulcerative colitis [UC], and studied the efficacy of DES1, a small-molecule inhibitor of Kv1.3, in vitro and in vivo.
Methods: Kv1.3 expression on T cells in peripheral blood mononuclear cells [PBMCs] isolated from donors with and without UC was examined by flow cytometry. In biopsies from UC patients, Kv1.3-expressing CD4+ T cells were detected by flow cytometry and immunohistochemistry. In vitro, we determined the ability of DES1 to inhibit anti-CD3-driven activation of T cells. In vivo, the efficacy of DES1 was determined in a humanised mouse model of UC and compared with infliximab and tofacitinib in head-to-head studies.
Results: Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of TH1 and TH2 T cells. Kv1.3 expression was also detected on T cells from biopsies of UC patients. In vitro, DES1 suppressed anti-CD3-driven activation of T cells in a concentration-dependent manner. In vivo, DES1 significantly ameliorated inflammation in the UC model and most effectively so when PBMCs from donors with higher levels of activated T cells were selected for reconstitution. The efficacy of DES1 was comparable to that of either infliximab or tofacitinib.
Conclusion: Inhibition of Kv1.3 [by DES1, for instance] appears to be a potential therapeutic intervention strategy for UC patients.


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