Oral Fingolimod May Reduce the Damaging Effects of MS

PRAGUE—Fingolimod (FTY720) may reduce neurodegeneration and enhance repair of the CNS damage caused by multiple sclerosis (MS), according to preclinical data presented at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Fingolimod down-regulates expression of sphingosine-1-phosphate (S1P) receptor-1. Researchers have theorized that its mechanism stems from reduction of lymphocyte S1P receptor-1, which slows the release of lymphocytes from peripheral lymph nodes, thereby reducing the potential for T-cell penetration of the CNS. However, S1P receptors also are expressed in the CNS, including on oligodendrocytes, and because fingolimod crosses the blood-brain barrier, there is potential for it to have direct effects on the cells of the brain.

“Mature oligodendrocytes form the myelin sheaths” and are therefore important cells in the pathogenesis of MS, according to Carmen Barske, a researcher at the Novartis Institutes for BioMedical Research in Basel, Switzerland, and colleagues. Using primary rat oligodendrocyte precursor cells and mouse stem cell–derived oligodendrocyte cultures, Ms. Barske and colleagues found that fingolimod increased the number of both immature and mature oligodendrocytes, including myelin basic protein-positive mature oligodendrocytes, “which represent the myelin-forming cell lineage.

“We propose that phosphorylated FTY720–mediated stimulation of S1P receptors on oligodendrocytes may help limit demyelination and/or promote remyelination in MS,” the researchers reported. “These direct effects of phosphorylated FTY720 on oligodendrocytes may contribute to its effectiveness in MS and limit disease progression.”

In another study of FTY720, Veronique Miron, a senior analyst in the Department of Neurology and Neurosurgery at McGill University in Montreal, and colleagues examined the effects of fingolimod on human fetal CNS-derived oligodendrocyte progenitor cells (OPCs). They explained that remyelination is dependent on OPCs rather than on previously myelinating oligodendrocytes. Their results showed that fingolimod “can exert dose- and time-dependent effects on OPC process extension, differentiation, and survival, which are all presumed important cellular events in remyelination.” Chronic administration of fingolimod “induced process extension and increased cell survival” and also inhibited OPC differentiation into a more mature oligodendroglial phenotype. They concluded that their findings “support the need to define the potential impact of chronic FTY720 therapy on remyelination in MS and to consider how S1P signaling may be used as a potential approach to remyelination.”

Florian Mullershausen, PhD, of the Novartis Institutes for BioMedical Research in Basel, and colleagues looked at the role of S1P receptors in astrocyte cell cultures. “These cells migrate throughout the brain and maintain the blood-brain barrier via communication with endothelial cells, and also promote both neuronal survival and oligodendrocyte myelination,” the researchers explained. Their investigation revealed that astrocytes express S1P receptors 1 and 3 and that fingolimod “induces Ca2+ signaling and activates S1P1/Gi and S1P3/Gq signaling to adenylyl cyclase and phospholipase C in astrocytes.” Fingolimod also promoted migration of astrocytes and regulated the phosphorylation of extracellular receptor-regulated kinase and Connexin 43 gap junction protein. They concluded that fingolimod “has multiple modes of action, beyond immunomodulation, which contribute to its effectiveness in MS.”

Preclinical research further supports a possible role for fingolimod in promoting remyelination. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, fingolimod delivered directly into the brain after disease onset suppressed the severity of the illness in the absence of peripheral lymphocyte reduction. “This was associated with enhanced myelination and axonal protection,” according to Anna Schubart, PhD, of the Max Planck Institute for Neurobiology in Martinsried, Germany, and colleagues. “This raises the possibility that FTY720 might also have protective effects in progressive stages of the disease.”

Shannon Gardell, PhD, and colleagues from the Molecular Biology Department of Scripps Research Institute in La Jolla, California, have been working with “mouse knockouts of single S1P receptor subtypes in monophasic EAE” to determine which S1P receptor and cell types are most relevant in EAE and, by extension, in MS. They found that deletion of S1P1 from neural cells attenuated, but did not eliminate, EAE.

Peter Hiestand, PhD, of Novartis Institutes for BioMedical Research in Vienna, and colleagues found that induction of relapses in EAE is attributable to an increase in blood vessels in the spinal cord, particularly “in the gray matter of the lumbar section of the spinal cord, suggesting that this region is of particular importance to the paralytic episodes observed in EAE in rats.” They also found that “treatment with FTY720, either from the time of disease induction or starting after recovery from the acute disease bout, led to a blockade of disease-induced neo-angiogenesis and complete inhibition of relapse formation.”

In a separate abstract, Dr. Hiestand compared fingolimod with interferon-beta and glatiramer acetate in the murine model of EAE. Fingolimod inhibited the onset of acute EAE, and if given after resolution of the acute bout, it prevented relapses. In comparison, glatiramer did not prevent acute onset of EAE, nor did it reduce the frequency or severity of relapses. Given during an acute episode, fingolimod prevented chronic progressive EAE, whereas interferon-beta did not. The disease reoccurred when fingolimod was stopped.

Harald Pohlman, MSc, of Novartis Pharmaceuticals in Basel, and colleagues used statistical modeling of the 24-month MRI and relapse data from the phase II study to characterize the time course of the benefits that were observed. Their findings suggest that fingolimod produces a rapid decrease in relapse frequency during the first six months of treatment, after which the rate is maintained at a consistently reduced level throughout the 24 months. Similarly, reductions in disease activity evident on MRI occurred rapidly, with half the maximal response achieved within the first month.

NR