Treating multiple sclerosis (MS) with Tecfidera (dimethyl fumarate) induces specific genetic alterations that may reduce the levels of immune T-cells targeting the central nervous system, researchers report.
Their study, “Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis,” was published in the journal Brain.
Environmental stimuli may induce epigenetic changes in cells — meaning not alterations in the genes themselves, but changes in gene expression (the process by which information in a gene is synthesized to create a working product, like a protein).
Epigenetic changes may induce MS development, as these alterations can cause T-cells to attack the central nervous system. One type of epigenetic change is DNA demethylation, the removal of methyl chemical groups, in which molecules involved in metabolism (such as fumarate) interact with enzymes known as DNA demethylases. This process in key for T-cell activation, function and memory, suggesting that it could be an immunomodulatory target.
Fumaric acid esters (FAEs) were shown to be effective in MS clinical trials, leading to the approval of Tecfidera (by Biogen) for people with relapsing-remitting forms of the disease. However, their complete mechanism of action remains unclear.
Aiming to address this gap, scientists at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York and the Icahn School of Medicine at Mount Sinai, recruited 98 MS patients, either previously untreated (47 people, mean age of 38.4), treated with Tecfidera (35 people, mean age of 42.3), or treated with glatiramer acetate (16 patients, mean age of 43.4) — marketed as Copaxone by Teva Pharmaceuticals, with generic forms by Sandoz (as Glatopa) and by Mylan.
All patients had stable disease for at least three months, but disease duration was shortest in untreated patients — 40.4 months vs. 130 months in those given Tecfidera, and 100 months in patients using glatiramer acetate.
Blood samples were collected from each participant to assess epigenetic changes in T-cells expressing the cell surface marker CD4. MS patients typically have an activated form of these cells in their blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord.
Results revealed that, compared to the other two groups, treatment with Tecfidera was associated with a lower percentage of T-cells containing the CD3, CD4, and CD8 markers, as well as lower levels of subsets of T-cells expressing the CCR4 and CCR6 receptors, which are critical to T-cell migration to the gut, brain, and skin.
Treatment with glatiramer acetate resulted in significantly milder alterations in T-cell percentages compared to no treatment.
Researchers then found that FAEs induce excessive methylation — the addition of methyl groups — in T-cells containing CD4, compared to glatiramer acetate. Specifically, this overmethylation was observed in a micro-RNA — tiny RNA molecules than control gene expression — known as miR-21, key for the differentiation of a subset of T-cells called T helper-17 (Th17) cells and for CCR6 expression in MS mouse models. These Th17 cells are critical in tissue inflammation and destruction, and have been implicated in MS.
The epigenetic effects of FAEs were subsequently validated by comparing pre- to post-treatment with Tecfidera in seven patients. In turn, in vitro (lab dish) experiments showed that FAEs act specifically on the activation of naïve T-cells — those able to respond to new pathogens to the immune system — containing the CD4 or the CD8 markers.
Of note, patients with MS have shown increased miR-21 levels, particularly during acute relapses. As such, the team hypothesized that its hypermethylation by FAEs could contribute to remission and the prevention of relapses in this patient population.
These results “suggest that the metabolic-epigenetic interplay in T-cells could be harnessed for therapeutic purposes,” the researchers wrote, and that the immunomodulatory effect of FAEs in MS is due at least in part to the epigenetic regulation of T-cells.
The researchers believe that their findings have a broader implication, beyond MS.
“Our findings about therapeutically active metabolites have implications for the treatment of not only multiple sclerosis but also other autoimmune diseases, such as psoriasis and inflammatory bowel disease, which involve the same type of T-cells,” Achilles Ntranos, the study’s lead author, said in a press release.
“Understanding the epigenetic effect of metabolites on the immune system will help us develop several novel strategies for the treatment of autoimmune diseases, which could help patients and physicians achieve better clinical outcomes,” Ntranos added.
Patrizia Casaccia, the study’s senior author, concluded: “It may one day be possible to target and suppress production of the specific brain-homing T-cells that play a role in the development of MS.”
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