Patricia Inacio, PhD, science writer —

By tweaking stem cells in a laboratory, researchers were able to generate a model of the human blood-brain barrier (BBB) in a chip. The BBB is a highly selective barrier that is damaged in multiple sclerosis (MS), allowing immune cells to reach the central nervous system and damage…

Aubagio (teriflunomide), an approved medicine for relapsing forms of multiple sclerosis (MS), specifically targets highly metabolic and more autoreactive T-cells, analysis of the Phase 3 TERI-DYNAMIC clinical trial data shows. The findings, contrary to expectations, support a selective effect of Aubagio on different T-cell populations. The study “Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects” was published in the Science Translational Medicine journal. In MS, immune cells, or lymphocytes known as T-cells, attack and destroy myelin, the fat-rich substance that wraps around nerve fibers (axons). Myelin loss creates lesions that affect nerves of the brain and spinal cord. Previous evidence suggested that T-cells, depending on their active or resting state, rely on specific ways of energy production or metabolism. Aubagio, marketed by Sanofi Genzyme, is a well-known inhibitor of a mitochondrial enzyme called dihydroorotate dehydrogenase (DHODH), that is crucial for the activity of T-cells. However, how Aubagio selectively targets the autoreactive T-cells is poorly understood. To shed light on this matter, an international group of researchers used data from the TERI-DYNAMIC clinical trial that tested Aubagio in patients with relapsing form of MS to better understand how the therapy inhibited the patients' self-immune responses. The Phase 3, open-label TERI-DYNAMIC trial (NCT01863888) included 70 patients from Belgium, Germany, and The Netherlands, aged 18 to 56. Participants received Aubagio as a 14 milligram (mg) once-daily, oral dose, and researchers assessed the changes in immune cells' profile up to 24 weeks. Results showed that, contrary to what was expected, Aubagio was not generally decreasing T-cell levels in treated patients. Instead, it significantly reduced a particular subset of T-cells, called "Th1 helper cells." Moreover, researchers found that the diversity of T-cell receptors — the surface proteins that can recognize a particular antigen (a protein that can elicit an immune response) — making T-cells specific to a certain target was reduced in MS patients after treatment with Aubagio. These findings suggested that some T-cells were particularly susceptible to Aubagio. Using a mouse model for MS, the experimental autoimmune encephalomyelitis (EAE) model, researchers showed that the CD4+ T-cells (helper T-cells) and CD8+ T-cells, those that reacted most strongly against self-antigens, were the most sensitive to DHODH inhibition by Aubagio. Moreover, researchers saw that Aubagio was not affecting the production of pro-inflammatory molecules — called cytokines — at the cell level, but their overall decrease probably was due to the reduction in T-cell numbers. In line with these findings, CD4+ T-cells that produced the cytokine interferon gamma were significantly reduced with Aubagio treatment, whereas CD4+ T-cells that produced interleukin 17A were unchanged. This suggests that Aubagio is able to interfere with specific sub-types of immune cells. When the team compared the metabolic profile of T-cells from healthy subjects with that from patients with relapsing-remitting MS (RRMS) in both remission and in relapse phases, they found that the metabolism of T-cells from the last group was significantly altered, and thus targetable. Altogether, the results suggested that T-cells with a high-affinity to self-antigens are more susceptible to inhibition of the DHODH enzyme by Aubagio. “Therapeutic targeting of metabolic alterations might represent an attractive concept in MS, and might represent an as yet unrecognized key mechanism of teriflunomide-mediated immune modulation in this disease,” the researchers concluded.

The pro-inflammatory protein interleukin-17 (IL-17) drives inflammation by promoting a chemical modification, called phosphorylation, in the RNA molecule of the regnase-1 enzyme, a mouse study shows. These findings support the development of therapeutics that block the phosphorylation of regnase-1 to halt IL-17-mediated inflammation, as seen in multiple…

Vumerity (diroximel fumarate), taken as a 462 milligram (mg) tablet twice daily, significantly decreases disease activity in patients with relapsing-remitting multiple sclerosis (RRMS), and leads to low rates of gastrointestinal side effects, new interim data of Phase 3 trial EVOLVE-MS-1 show. The findings were presented at the 2019 Consortium…

The latest research in multiple sclerosis (MS), along with the most recent advancements in treatment strategies and comprehensive care, will be presented at the Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, which beings today. Running through June 1 at the Washington State Convention Center in Seattle, the…

Aubagio taken as 14 milligram (mg) tablet once daily significantly reduces the risk of relapse in people with relapsing multiple sclerosis (MS) over time irrespective of their prior treatment history, a pooled analysis of Phase 2 and Phase 3 trial results show. The findings were presented at the 2019…

Giving estrogen to two different adult mouse models of multiple sclerosis (MS), including the experimental autoimmune encephalomyelitis (EAE) model, promoted remyelination, a new study shows. Exposure to the hormone affected gene activity in oligodendrocytes, tricking them into producing myelin (the fatty substance that protects nerve cells, and that is destroyed…

Oligodendrocyte precursor cells (OPCs), the cells responsible for myelin production, are unable to migrate into sites of myelin loss in the brain. These cells then cluster and disrupt the blood-brain barrier (BBB), triggering an inflammatory process in the early stages of multiple sclerosis (MS), a study shows. The study, “Aberrant oligodendroglial–vascular interactions disrupt the blood–brain barrier, triggering CNS inflammation,” was published in the journal Nature Neuroscience. MS is an autoimmune disease characterized by the loss of myelin (demyelination) — the fat-rich substance that protects nerve fibers — which leads to neurodegeneration. Along with loss of myelin, researchers have observed that the blood-brain barrier — a highly selective membrane that shields the central nervous system with its cerebrospinal fluid from the general blood circulation — breaks down in the initial stages of disease. A team led by researchers at the University of California, San Francisco, have now discovered that OPCs are involved in the disruption of the blood-brain barrier in MS, according to a press release from the National MS Society, which funded the study. Oligodendrocytes are myelin-producing cells and are responsible for myelinating the nerve cells’ axons — a single oligodendrocyte is capable of myelinating multiple axons. Mature myelin-producing oligodendrocytes develop from more immature, stem cell-like OPCs. In a normal brain, upon myelin loss, OPCs are called into action and travel into the damage site where they mature and generate myelin-producing oligodendrocytes. In this study, the researchers found that OPCs in MS form clusters in blood vessels of the brain-blood barrier, having lost the ability to detach from these vessels and migrate to injury sites. In an animal model of MS, they saw that OPC aggregates altered the location of other cells — called astrocytes — in a competition for space, and contributed to the disruption of blood vessels. Astrocytes are a group of star-shaped cells, belonging to the group of glial cells, that provide neurons with energy, and work as a platform to clean up their waste. They also have other functions within the brain, such as regulating blood flow and inflammation. The team also observed that OPC aggregates trigger an immune inflammatory response, shown by a large number of microglia (the central nervous system immune cells) and immune cells called macrophages around these cell clusters. “We find in several MS cases, in lesion areas with active inflammation, that OPCs can be found clustered on vasculature, representing a defect in single cell perivascular migration and inability to detach from blood vessels,” the researchers wrote. Further molecular analysis revealed that OPCs have high levels of Wnt signaling, and elevated secretion of Wif1 factor to the extracellular space that could explain why OPCs accumulate and destroy the blood-brain barrier. The WiF1 factor is actually a negative regulator of Wnt signaling that is essential for the maintenance of the blood-brain barrier structure. This factor competes with Wnt ligands, and affects the integrity of cellular junctions, making the blood-brain barrier more fragile and permeable. "Evidence for this defective oligodendroglial–vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB,” the researchers wrote. They suggested that more studies are needed to better understand the interactions between blood vessels and oligodendrocytes, which could help identify new therapeutic targets for promoting myelin repair in MS.

Tecfidera (dimethyl fumarate) is more efficient at preventing relapses, and has a lower discontinuation rate than Aubagio (teriflunomide), according to a Danish study. The study “Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study” was published in the journal Neurology. Aubagio (marketed by Sanofi Genzyme) and Tecfidera…

Gabapentin and pregabalin now have more restrictive rules for prescriptions in the United Kingdom. Because of concerns regarding the medications’ misuse, both were classified as class C controlled medicines. It is now illegal to supply, sell, or possess these medicines without a prescription, according to a news release by…

The U.S. Food and Drug Administration (FDA) has approved Novartis’ Mayzent (siponimod) oral tablets for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease (SPMS). Mayzent was designed to inhibit the activity of…

A daily cup of flavonoid-rich cocoa may help ease fatigue in people with relapsing-remitting multiple sclerosis (RRMS), according to the results of a small clinical trial. The study “A randomised double-blind placebo-controlled feasibility trial of flavonoid-rich cocoa for fatigue in people with relapsing and remitting multiple sclerosis” was…

Women diagnosed with multiple sclerosis (MS) say they lack guidance regarding family planning, pregnancy, and breastfeeding, according to a survey. Sixteen percent of those women also reported they didn’t become pregnant due to MS-related concerns. Casey E. Engel,  clinical researcher at Weill Cornell Medical College in New York,  presented the…

Full results of a Phase 2 clinical trial testing TG Therapeutics’ lead candidate ublituximab (TG-1101) for relapsing multiple sclerosis (MS) showed that treatment for 48 weeks resulted in a marked reduction of brain and spinal cord lesions, an almost complete depletion of relapse-associated immune B-cells, and significantly halted disability…

Evobrutinib, Merck KGaA’s oral candidate for relapsing multiple sclerosis (MS), is safe and can significantly reduce active brain lesions over 24 weeks of treatment, results of ongoing Phase 2 study show. Xavier Montalban, PhD, MD, with Vall d’Hebron University Hospital in Barcelona, presented the results in the talk “Primary…

Podocalyxin, a protein found in cells lining the interior of blood vessels, is key for maintaining the integrity of the blood-brain barrier (BBB) in mice with systemic infection, suggesting its potential as a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS), a study shows. Disruption of the…

Multiple sclerosis (MS) patients given intensive disease-modifying therapies early in their disease course have more favorable long-term outcomes than those treated with an escalating regimen, real-world data shows. The study, “Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis,” was published in the journal …

The RhoE protein has been identified as being important for axons’  myelination and extension in the central nervous system, two processes that go awry in diseases like multiple sclerosis (MS). The findings stem from Pilar Madrigal’s doctoral thesis, “Role of the small GTPase RhoE in myelination and axonal tracts development.”…

Genetic variants that enhance the activity of the NLRP3 inflammasome or the interleukin-1 beta cytokine are linked to higher severity and progression of multiple sclerosis, a study suggests. Previous studies with mouse models of MS have shown that a complex of innate immune system receptors and sensors, known as the inflammasome, is likely a player promoting the immune system’s attack on the central nervous system in MS and, consequently, the loss of myelin. Follow-up studies showed that people carrying mutations that enhance the function of the NLRP3 inflammasome — one of the three components of the inflammasome complex — had a worse prognosis, once again supporting the role of the inflammasome in MS. Once activated, the inflammasome triggers an enzyme called caspase-1 that promotes the production of two very powerful proinflammatory cytokines called interleukin (IL)-1 beta and IL-18. To further evaluate the role of the inflammasome in MS, a team led by researchers at the Universidade de Sao Paulo in Brazil analyzed the genetic sequence of five inflammasome genes — NLRP1, NLRP3, NLRC4, IL-1 beta, and IL-18 — in blood samples retrieved from 264 patients diagnosed with MS or other demyelinating diseases. They also analyzed 233 healthy individuals used as controls. The team specifically looked at eight variations in certain nucleotides (the building blocks of DNA), called single nucleotide polymorphisms (SNPs). Previous studies reported a link between SNPs in inflammasome-related genes and certain forms of MS. Results showed that SNPs associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls. In contrast, variants that enhance the function of NLRP3 and IL-1 beta were associated with severity and progression of MS, as measured by the Expanded Disability Status Scale. These results suggest that the "activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation,” the researchers wrote. A particular variant in the NLRC4 gene was less frequent in patients whose disease progressed rapidly compared with those who had a slower disease, an intriguing observation, according to researchers, suggestive of a “protection effect of this variant against a bad prognosis.” Carriers of this variant also responded better to treatment with interferon-beta. Regarding MS type, the genetic variant that promotes the function of the IL-1 beta gene was significantly more frequent in progressive forms of MS than in relapsing-remitting MS, strengthening once again the negative effects of IL-1 beta in the disease. An analysis of inflammasome activity in blood monocytes, a group of immune cells, showed that the inflammasome is permanently activated in MS compared with healthy controls. "This study emphasizes that a constitutive activation of NLRP3 inflammasome, principally through IL-1 beta production, represents a risk factor for both the development of MS and the progression to severe forms of the disease. On the other hand, low IL-18 production and/or NLRC4 activation were beneficial for MS patients,” the team concluded.

Stem cells tweaked in the laboratory have allowed researchers, reportedly for a first time, to generate and maintain ball-shaped cultures — called spheroids — of human brain cells in 3D that contain oligodendrocytes, the cells that produce myelin, along with neurons and the astrocytes that are essential to nerve cell health.

Gilenya is linked to significantly lower annualized relapse rates in relapsing-remitting multiple sclerosis (RRMS) patients compared to Tecfidera or Aubagio, a study suggests. All three therapies showed similar effects on disability outcomes. Oral immunotherapies — including Novartis’ Gilenya, Biogen’s Tecfidera, and Sanofi Genzyme’s Aubagio — are currently standard therapies for RRMS treatment. But while these therapies are highly effective at modulating MS activity, studies comparing their efficacy on relapse and disability are missing. This is an important point for MS patients, so that if a change in oral therapies is needed (due to lack of tolerance, for example), the decision on a more suitable therapy is based on scientific evidence. To address this matter, a group of researchers used the MsBase, an international observational MS cohort study, to identify RRMS patients who had been treated with Gilenya, Tecfidera, or Aubagio for at least three months. The team compared Tecfidera versus Aubagio, Gilenya versus Aubagio, and Gilenya versus Tecfidera, specifically for the therapy’s impact on relapse activity, six-month disability worsening or improvement, and persistence of treatment. Relapse was defined as the occurrence of new symptoms or exacerbation of existing ones for a period of over 24 hours, at least 30 days after a previous relapse. Disability was assessed using the Expanded Disability Status Scale (EDSS); the six-month disability worsening or improvement were defined as an increase or a decrease by one value in EDSS. The study included 614 patients treated with Aubagio, 782 with Tecfidera, and 2,332 with Gilenya. Patients were followed over a median of 2.5 years. Patients’ characteristics at baseline differed among the three groups. Aubagio-treated patients tended to be older, with longer periods of disease, fewer relapses, and lower EDSS scores compared to the other two groups. Patients treated with Gilenya had higher EDSS and more relapses during the prior year, compared to those treated with Tecfidera. The majority of the patients had been treated with other immunotherapies prior to being given one of these three oral treatments. Results showed that Gilenya-treated patients had significantly lower annualized relapse rates than those treated with Tecfidera (0.20 versus 0.26) or Aubagio (0.18 versus 0.24), while patients taking either Tecfidera or Aubagio had a similar rate. However, during the 2.5-year period analyzed, researchers found no differences in disability accumulation or disability improvement among the three therapies. Regarding treatment persistence, Tecfidera and Aubagio were more likely to be discontinued than Gilenya. Overall, the results suggest that treatment with Gilenya may have a greater impact on relapse frequency in RRMS patients compared to Tecfidera and Aubagio, although the "effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment," researchers said. “Choosing a therapy in individual patients remains a complex task that requires thorough and individualized evaluation of disease prognosis, and the corresponding risks and benefits of the increasing number of available therapies,” they concluded.

Endothelial cells, those lining the inside of small blood vessels, promote clearance of myelin debris — a common detrimental outcome of demyelinating diseases such as multiple sclerosis (MS) or spinal cord injury. However, in its path to clear the brain from myelin debris, endothelial cells trigger more damaging mechanisms, promoting…

Autologous hematopoietic stem cell transplant is better than disease-modifying therapies (DMT) at reducing the risk of disease progression in patients with relapsing-remitting multiple sclerosis (RRMS), results from the MIST clinical trial show. The study “Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression…

Treating a common animal model of multiple sclerosis (MS) with a typhoid vaccine eased disease symptoms by prompting T helper cells to stop production of a pro-inflammatory factor — interleukin (IL)-17 — and by promoting greater numbers of anti-inflammatory  regulatory T-cells, researchers report. Their study, “Targeting prohibitins at the…

Blood infection with the yeast Candida albicans, a type of fungus, can reach the brain and trigger an immune response, a new mouse study shows. Although the fungus can be cleared within 10 days, it affects the spatial memory of mice. These findings are the first evidence that a blood infection with a…

Immune cells in the intestine may reduce neuroimflammation in multiple sclerosis (MS) patients, a pre-clinical study suggests. Moreover, the augmented number of these cells was sufficient to suppress brain inflammation in an MS mouse model. The findings were reported in the study “Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via…

Unusually high levels of a transcription factor called paired related homeobox protein 1 (PRRX1) in human oligodendrocyte progenitor cells hinders their ability to respond to the loss of myelin and to transform into mature, myelin-producing oligodendrocytes, a new study shows. These findings suggest a new potential way of treating …

Treatment with autologous hematopoietic stem cell transplant (aHSCT) led to a sustained decrease in disability and almost no clinical relapses in patients with relapsing-remitting multiple sclerosis (RRMS) who had failed to respond to prior immunosuppressive therapies, an Australian Phase 2 trial shows. Trial findings were published in the study, “Prospective phase…

A genetic variant associated with an increased risk of multiple sclerosis (MS) due to its impact on certain immune system cells can also affect brain cells called astrocytes, a study shows. Reported in the study, “Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple…

Microglia, the resident immune cells of the brain, were seen to change throughout the lifespan of mice in a study — and to be diverse, with distinct cell subtypes. Those with pro-inflammatory behavior may be disease-causing, as they were found to accumulate in the brains of a mouse model of…