According to new studies published online 27th of August, 2021 (Karsten et al., MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells; Springer Nature, CDDpress), Karonudib/TH1579 shows proof of therapeutic concept in T cells driven Experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis (MS).
For full text access to a view-only version: https://rdcu.be/cwcfD.
Many autoimmune diseases, like MS, psoriasis, rheumatoid arthritis, inflammatory bowel disease and type 1 diabetes are to a large extent T cell driven (1). Just like many cancer cells, activated T cells are associated with increased ROS levels and an upregulated glycolytic switch (2-4). MTH1 is up-regulated in activated T cells as compared to non-activated T cells (5). Therefore, in the study, it was hypothesized that activated T cells, like cancer cells, would be sensitive to treatment with Karonudib, whereas resting T cells would be resistant due to their lower expression of MTH1. Indeed, in preclinical models, Karonudib is killing activated T cells (6). Interestingly, Karonudib is selective for activated T cells while other cells of the immune system are rather unaffected.
Karonudib (and other MTH1 inhibitors) furthermore show improvement in a psoriasis disease model (7). A topical formulation has been developed for Karonudib and is presently evaluated in a psoriasis disease model.
(1)Wang et al., J Intern Med 2015; 278:369-95;
(2) Raphael et al., Cytokine, 2015:74:5-17
(3) Gambhir et al., International Immunopharmacology 2019; 67:449-57;
(4) Previte et al., Plos One, 2017;12.
(5) Oda et al., J Biol Chem 1997; 272:17843-50
(6) Karsten et al., Cell Death and Differentiation, in press (For full text access to a view-only version: https://rdcu.be/cwcfD )
(7) Eding et al., J Invest Dermatol 2021 Aug;141(8):2037-2048.e4