Epigenetic interventions with hypomethylating agent 5-aza-2-deoxycytidine in preclinical models of multiple sclerosis

Multiple sclerosis (MS) is an immunoinflammatory disease, that affects the central nervous system (CNS) and that is characterized by inflammatory lesions, demyelination, and axonal loss. The Experimenal allergic encefalomyelitis (EAE) models are commonly used to characterize the etiopathogenic mechanisms of MS, and to screen the efficacy of new therapies. Numerous evidences from EAE support the idea that effector Tregs markedly influence the threshold of disease progression and contributes to the natural recovery from actively-induced EAE. Also, it has been established that accumulation of Tregs in the CNS precisely correlates with the recovery phase. It has been recently found out that epigenetic modifying agents, such as 5-aza-2- deoxycytidine, are able to modulate the expression of FoxP3 in naive CD4+/CD25- T cells1. During DNA replication, the methylation pattern of the parental DNA strand is copied to the new-synthesized strand by the enzyme methyltransferase DNMT1, and makes genes either active or silent. 5-aza-2-deoxycytidine (DAC, decitabine) and other molecular variations of deoxycytidine, modified at position 5 of the pyrimidine ring, are known methylation inhibitors. DAC is initially activated by deoxycytidine kinase from a monophosphate form to the active triphosphate form, which is then incorporated into DNA by DNA polymerase. Once incorporated into the DNA, it binds covalently to methyltransferases and inactivates them, inducing substantial replication-dependent DNA hypomethilation2. DAC received approval from the U.S. Food and Drug Administration for the treatment of myelodiplastic syndromes and chronic myelomonocytic leukemia in 2006.Aim of this study is to assess the efficacy of DAC administration in the different clinical forms of EAE (Relapse-remitting, primary-progressive and secondary-progressive) in order to find novel therapeutic strategies to be used for the treatment of MS.