Treatment with Mayzent (siponomod) may reduce myelin deterioration by lessening the accumulation of immune cells in brain meninges, and preventing the migration of pro-inflammatory lymphocytes into the brain, according to a study in a mouse model of multiple sclerosis (MS).
The research, “A Mouse Model of Meningeal Inflammation and Subpial Demyelination Identifies an IL-17-mediated Mechanism of Cortical Injury that is Inhibited by Siponimod Therapy,” was presented recently at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia (May 4-10). The data were presented by Valeria Ramaglia, PhD, research associate at the University of Toronto, Canada.
Loss of myelin, the protective layer of nerve fibers, in the brain’s outer layer (the cortex) is characteristic of MS. A particular type of cortical demyelination, called subpial, is associated with MS progression and cognitive decline. Although inflammation at the meninges — a three-layer structure that protects the brain and spinal cord — has been proposed as a key event, the precise mechanisms leading to disease-related alterations remain unclear.
A team from Switzerland and Canada used a new mouse model of subpial demyelination and meningeal inflammation to address this question.
To assess whether migration of lymphocytes (specific immune cells) from the periphery into the brain could be involved, investigators treated mice with Mayzent (marketed by Novartis), which, by binding to S1P receptors, trap lymphocytes in lymph nodes and prevent them from reaching the brain. Results of the Phase 3 EXPAND trial (NCT01665144) showed that treatment with Mayzent lessened the risk of disability progression in patients with secondary progressive MS (SPMS).
Experimental autoimmune encephalomyelitis (EAE), the mouse model of MS, was induced in mice by transferring a subtype of immune T-helper (Th) cells called proteolipid protein-specific Th17 cells. This led to alterations in connective tissue cells known as stromal cells, and build-up of specific immune B- and T-cells (containing the B220 and CD3 markers, respectively) in the brain meninges.
These immune cells were found to be in the same areas of subpial cortical demyelination associated with activation of other immune cells known as microglia and macrophages, as well as with astrogliosis — injury-induced changes in astrocytes, the most abundant cells in the central nervous system (CNS) — and disruption of the glia limitans.
Of note, similar to the blood-brain barrier, the glia limitans membrane prevents the migration of cells and other large molecules into the CNS.
Then, treatment with Mayzent significantly lessened disease-related alterations in mice, reducing meningeal inflammation and subpial changes. Also, Mayzent lowered the number of transferred T-cells that migrate to the CNS. This effect was specific for T-cells containing the CD45 protein and producing the pro-inflammatory molecule interleukin (IL)-17.
“We conclude that the recently reported protective effects of siponimod [Mayzent] in MS may be mediated by a reduced accumulation of immune cells in the meninges, suppression of IL-17-producing lymphocytes in the CNS, and a concomitant reduction in demyelination and inflammation in the supbial cortex,” the researchers wrote.
According to Ramaglia, a reduction in the accumulation of IL-17-producing T-cells “provides a potential mechanism of action for siponimod in MS.”
Mayzent was approved in March 2019 by the U.S. Food and Drug Administration (FDA) as a treatment for adult patients with relapsing MS forms, including clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active SPMS.