Patricia Inacio, PhD,  science writer—

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…

Non-viral vehicles, called niosomes, can deliver DNA to glial cells in the central nervous system, a new study shows. The findings open new avenues for gene therapy and the treatment of neurological disorders, including multiple sclerosis (MS). The study “Non-viral vectors based on cationic niosomes as efficient gene delivery…

Aspirin, administered orally at low doses, was sufficient to suppress multiple sclerosis (MS) symptoms in a mouse model of relapsing-remitting MS (RRMS) and chronic MS, a study reports. The clinical benefits of aspirin were linked to an increase in the number of regulatory T-cells, those responsible for shutting…

The formation of new myelin sheaths by oligodendrocytes is impaired in the absence of a small molecule, called Vav3, that oversees pathways regulating the shape of oligodendrocytes, new study reports. Its researchers pinpoint Vav3 as a potential therapeutic target to improve and speed myelin repair in diseases like multiple sclerosis…

Mature, adult oligodendrocytes can reacquire their ability to produce myelin to replace the ones lost in diseases like multiple sclerosis (MS) without undergoing a stem cell-like state, a new study shows. Myelin is the fat-rich substance that wraps around nerve fiber projections (axons) protecting them and increasing the speed of…

High levels of certain lipids, or fat, in the blood are linked to increased disability scores and high levels of pro-inflammatory markers in relapsing-remitting multiple sclerosis (RRMS) patients, a small study reports. The study, “Lipoprotein markers associated with disability from multiple sclerosis,” was published in the journal Scientific…

Atara Biotherapeutics’ investigational ATA190, a cell therapy that wipes out immune B-cells infected with the Epstein-Barr virus (EBV), led to neurological improvements and reduced symptoms in patients with primary and secondary progressive multiple sclerosis (MS), a Phase 1 trial shows. The trial results were published in the Journal…

Women with multiple sclerosis are being diagnosed at younger ages and in greater numbers than men, except for those with primary progressive disease (PPMS), where men 50 or older tend to predominate, a European review study that looked at trends over several decades reports. The study “Age‐dependent variation of female…

The pro-inflammatory Th17 cells that characterize multiple sclerosis (MS) may also underlie symptoms of obsessive-compulsive disorder (OCD), results of a mouse study show. The study, “Auto-Reactive Th17-Cells Trigger Obsessive-Compulsive-Disorder Like Behavior in Mice With Experimental Autoimmune Encephalomyelitis,” was published in the journal Frontiers in Immunology. “For the first time,…

Blocking SARM1, a protein identified as a central mediator of nerve cell degeneration, works to prevent damage to axons — nerve cell fibers essential in cell-to-cell communication — and may be a way of treating neurodegenerative diseases like multiple sclerosis (MS), data from Disarm Therapeutics shows. Specially, genetically deleting…

Diabetes, hypertension, and active smoking correlate with more brain shrinkage in multiple sclerosis (MS) patients, a new study shows. The study, “Assessing the burden of vascular risk factors on brain atrophy in multiple sclerosis: A case- control MRI study” was published in the journal Multiple Sclerosis and Related Disorders.

Fast Forward, a nonprofit subsidiary of the National Multiple Sclerosis Society, will invest up to $330,000 to advance the clinical development of an antibody that was shown to lessen inflammation and nerve cell damage in a multiple sclerosis (MS) mouse model. The funding will help develop the antibody (a protein…

Infection with the most common member of the herpes virus family, called HHV-6, may pass unnoticed and without symptoms, but the very act of being infected significantly accelerated the development and progression of a multiple sclerosis-like disease in nonhuman primates, a study reports. Its findings support the role of viral infection in…

The rate of kidney deterioration as a result of bladder dysfunction due to multiple sclerosis (MS) is low, affecting only 3 percent of the patients, a single tertiary center study shows. However, kidney deterioration is a slow process and detected only after 60 months of follow-up, highlighting the need for…

Lymphatic vessels, the “roads” that work to clear waste material from the brain, can also carry messages that direct immune system attacks against myelin, promoting the onset of multiple sclerosis (MS), new study shows. While the identity of these messages remains unknown, the findings suggest that blocking these signals could…

GeNeuro announced it has reacquired from Servier the worldwide rights to commercialize and develop the investigational humanized antibody GNbAC1 for the treatment of multiple sclerosis (MS). The decision came after Servier, a European company which, together with GeNeuro, developed the GNbAC1 program, declined to continue developing the therapy due to…

Two years of treatment with oral Gilenya (fingolimod) significantly reduced the rate of relapses when compared to Avonex (interferon beta-1a) intramuscular injections in children and adolescents with relapsing forms of multiple sclerosis (RMS), according to Phase 3 clinical trial results. Additionally, Gilenya (marketed by Novartis) decreased the number of central nervous…

A meta-analysis of 13 case-control studies shows that the levels of the protein neurofilament light chain (NFL) are significantly higher in both the cerebrospinal fluid and blood of multiple sclerosis (MS) patients, compared to healthy controls. This finding adds to previous evidence supporting the usefulness of NFL as a…

Cerebrospinal fluid of progressive multiple sclerosis (MS) patients may carry lower levels of cell-free mitochondrial DNA, according to a team of researchers who say this may be a sign of neurodegeneration among these patients. The study “Cell-free mitochondrial DNA in progressive multiple sclerosis” was published in the journal Mitochondrion.