Understanding and mitigating the role of environmental influences that trigger changes in gene expression in disease development is a major goal of researchers. A new study details how metabolites can be used to inhibit epigenetic mechanisms and effectively treat multiple sclerosis. The discovery could lead to novel, more specific, and more effective MS therapies, and a better understanding of how the disease develops.

Dimethyl fumarate (Tecfidera) – a cell-permeable metabolite in the family of fumaric acid esters (FAEs) – is an approved treatment for MS. The precise mechanism of the drug's action has been only partially understood. In their new paper, researchers at the Advanced Science Research Center at the Graduate Center of the City University of New York and the Icahn School of Medicine at Mount Sinai take a major step toward unraveling the mystery by identifying a possible mechanism of action for FAEs.

Scientists believe that MS develops when epigenetic changes cause certain brain-homing immune cells – or T cells – to attack the central nervous system. In their current paper, researchers posited that FAE metabolites work by mitigating the development of certain brain-homing T cells.

Researchers recruited 97 volunteers with MS that either did not receive treatment, or were FAE-treated or glatiramer acetate-treated. Blood samples were collected from each participant and their levels of brain-homing T cells were measured by looking at the percentages of the chemokine receptors CCR4 and CCR6, which are critical to T cell trafficking between the gut, brain, and skin. The data showed significantly lower levels of these brain-homing T cells in the FAE-treated group than in the other comparison groups.

Researchers subsequently analyzed how FAEs change the epigenetic landscape of T cells to reduce the development of these pathogenic cells. They found that FAEs have a strong epigenetic effect on a particular DNA region in T cells that includes a micro RNA called MIR-21, which is necessary to create disease-linked brain-homing T cells. Taken together, the results suggest that the immunomodulatory effect of FAEs in MS is at least in part due to the epigenetic regulation of these specific brain-homing T cells.

The study was published published in the journal Brain.