Triacetyl-5-Azacytidine Suppresses Experimental Allergic Encephalomyelitis (EAE) in Mice

Background/Objectives: The epigenetic drug 5-azacytidine (AzaC) is being used for the treatment of myeloproliferative diseases. It has multiple immunomodulating activities: it enhances the activity of Treg cells and suppresses effector T cell proliferation and function. Our aim was to repurpose AzaC for the treatment of multiple sclerosis (MS). AzaC treatment of myelodysplastic syndrome often improves the autoimmune disorders accompanying it. Another epigenetic drug, decytabin, was effective in EAE, suggesting that AzaC might behave similarly. Earlier, we found that AzaC improves aggrecan-induced arthritis in mice, further supporting our hypothesis. Methods: AzaC was tested in an animal model of MS: MOG35–55-induced experimental allergic encephalomyelitis (EAE) in B6 mice. In addition to AzaC, its ester, prodrug triacetyl-5-azacytidine (TAC), reported earlier to exhibit improved stability and oral bioavailability, was also tested. Results: In our proof-of-concept experiment, i.p. administered AzaC ameliorated EAE. Then, we demonstrated that oral TAC is as effective as the positive comparator fingolimod. Next, we demonstrated that sub-optimal doses of oral TAC and fingolimod positively synergize. Importantly, the myelosuppression induced by TAC was not worse than that of the gold-standard fingolimod. Conclusions: Ours is the first study reporting the therapeutic activity of oral TAC. Both AzaC and TAC were effective in EAE; therefore, they can be proposed for the treatment of remitting–relapsing MS and possibly other autoimmune diseases. In addition, combination treatment with TAC and fingolimod might allow for lower individual drug doses, thus offering an alternative when side effects limit the use of current multiple sclerosis drugs.