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April 18, 2019 News by Patricia Inacio, PhD

Oligodendrocyte Precursor Cells Disrupt Blood-brain Barrier, Trigger Brain Inflammation in MS, Study Shows

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.

April 12, 2019 News by Marisa Wexler, MS

Excess Body Fat Spurs Disease Progression by Impact on Immune Cells, Study Suggests

A link between fat molecules called ceramides and worsening disease in overweight and obese people with multiple sclerosis appears to exist, a study reports, with its findings suggesting that ceramides prompt the growth of immune cells called monocytes, which in turn spurs disease progression. These results also strengthen the likelihood that lifestyle factors, like diet and weight, can act as disease modifiers, its researchers said. High body mass index has been linked to the risk of developing MS, but for reasons that aren't clear. One idea is that weight-induced differences in lipids (fat molecules) in the blood, because they are involved in several cellular signaling processes, may affect MS and its course in people with higher BMIs. To test this hypothesis, a team led by researchers at the Advanced Science Research Center (ASRC) at The Graduate Center and at the Icahn School of Medicine at Mount Sinai analyzed 54 patients with relapsing-remitting MS (MS), ages 18 to 60, and with normal or high BMIs (27 people in each group). Participants were followed for two years. BMI is a measure of body fat based on height and weight. A normal BMI is defined as one between 18.5 and 24.9, while a person is considered overweight with a BMI of 25–29.9, and obese it is 30 or higher. Researchers took blood samples, and looked for differences between the groups in terms of both immune cells and blood lipid profiles. They then validated their findings in a separate group of 91 RRMS patients. Patients with high BMIs tended to have more monocytes than those with normal BMIs. Monocytes can travel through the blood to tissues where they develop into macrophages, immune cells with various functions that are best known for "eating" invading bacteria. Monocytes can also travel to the brain and damage nerve fibers. Overweight and obese patients also had significantly higher levels of ceramides compared with normal-weight patients, and the researchers wondered if a link might exist between the two. Through a set of experiments in cells, they discovered that ceramides cause epigenetic changes in monocytes; that is, they alter the way their genomes are "read," so they alter gene activity. Specifically, ceramide-treated cells showed a type of epigenetic change called methylation — which generally turns genes "off" — in genes that normally help prevent cells from dividing. Conceptually, these genetic changes serve to unleash monocytes, leading them to grow more (proliferate) than they otherwise might. The researchers also found more methylation on the genomes of monocytes from high-BMI patients than those from low-BMI patients, and they noted that the overweight or obese patients also tended to have greater disease activity, worse disability progression, and more brain lesions on MRI (magnetic resonance imaging) scans on follow-up. Finally, the researchers tested a mouse model of MS, giving one group of mice a standard diet and another a high-fat diet. Mice fed the high-fat diet were found to have greater disease severity, more brain lesions, and more monocytes, confirming the findings seen in MS patients. "This study gives us a much-needed view into the environmental influences that can affect and change the behavior of cells in an individual's body," Kamilah Castro, the study's first author, said in a press release. "Our findings suggest that increased levels of saturated fat as a result of dietary habits are one likely cause of the epigenetic changes that advance MS, which gives us a starting point for a potential intervention." According to the team, the findings support the concept of nutri-epigenomics: that is, the ability of food to alter the way the genetic information is interpreted by each cell, and suggest that "weight management and dietary intervention" might affect MS prognosis. One limitation was the study's small size, its researchers noted. "While we consider our results … very exciting and mechanistic, we acknowledge that the potential consideration of ceramide levels as biomarkers for disease progression in MS would require validation ... using larger cohorts with a longitudinal and/or cross-sectional design," they concluded. "It will also be important to evaluate the effectiveness of dietary intervention (with an emphasis on the reduction of specific classes of saturated fats), as potential modulator of plasma ceramide levels and possibly of disease course in MS patients."

April 8, 2019 News by Jose Marques Lopes, PhD

Mayzent ‘Will Change Lives’ of MS Patients Transitioning to SPMS, Novartis Says

The “regulatory environment” favored Mayzent (siponimod) being approved as an oral treatment for people with relapsing multiple sclerosis (MS) — specifically, clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive MS (SPMS) — a top executive with Novartis said, although the pharmaceutical company had requested a label covering all with SPMS. Dan…

April 3, 2019 News by Marisa Wexler, MS

Cleveland Clinic Neurologist Applauds Mayzent’s FDA Approval, But Surprised by Those It May Not Treat

When the U.S. Food and Drug Administration approved the disease-modifying therapy Mayzent for relapsing types of multiple sclerosis, it specified in its label that the treatment was for people with clinically isolated syndrome, relapsing-remitting MS, and — importantly — secondary progressive MS provided they have "active" disease. The approval is good news, an MS researcher and physician said to Multiple Sclerosis News Today in an interview, but "surprising" in that the FDA's decision was largely based on a trial that didn't involve CIS patients and wasn't focused on responses among particular types of SPMS. “It's the first time that I've seen in the MS field that regulators made an approval designation — active secondary progressive MS — based on an underpowered subgroup analysis,” said Robert Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. Novartis' medication, as a first oral therapy approved in the U.S. for a form of SPMS, is a big step forward in MS treatment, he said. But details of the FDA's decision caught him off guard. Fox served on the steering committee for the EXPAND Phase 3 clinical trial , on which the FDA decision was largely based. His clinic was also one of the sites treating and evaluating patients in this pivotal study. Results of the EXPAND trial showed that Mayzent could reduce the risk of disability progression at three months (the trial’s primary endpoint, or goal) by 21% in treated SPMS patients, compared to those given a placebo. Among those with active SPMS (meaning with relapses), a 33% reduction was observed. The treatment, an S1P modulator that works in part to keep lymphocytes from entering the brain to trigger inflammation, also decreased the annualized relapse rate by 55% and improved cognitive processing speed in all treated patients.  “What was found, and I think quite clearly found in a large-size study, was that siponimod in patients with secondary progressive MS clearly slowed the progression of clinical disability over the course of the trial,” Fox said. “It's a statistical concept — obviously patients either progress or they don't progress — but on an overall basis there was a 21% slowing in the rate of progression of clinical disability.” The FDA’s decision is particularly important for SPMS patients. While Ocrevus (ocrelizumab) also treats all relapsing MS forms and people with primary progressive disease (PPMS), it's an intravenous therapy given every six months. Mavenclad (cladribine), approved for relapsing patients in the U.S. just days after Mayzent, is another oral and active disease therapy. To Fox, Mayzent seemed to reach beyond only those secondary progressive patients with clinically active disease. “Really, this is the only drug that's been found to be effective in secondary progressive MS," he said. “To that degree, it stands alone.” That's why two points in the FDA's decision surprised him. The first is the label's specific mention of clinically isolated syndrome. CIS is defined as the first clinical presentation of this disease — a neurological episode that lasts at least 24 hours, and is characterized by inflammatory demyelination (the loss of myelin, the protective coat surrounding neurons).   For clinicians like Fox, CIS is a first manifestation of MS — a kind of "mono sclerosis." Since there’s only one documented attack, it can’t yet be considered multiple sclerosis, “as the multiple hasn't happened,” Fox said, but many "in the field consider CIS to be … an early stage of MS." “If the patient has a whole bunch of lesions on their brain [as seen on an MRI scan] and they had a single clinical event, ah, probably, they have MS,” he said. Regulatory bodies like the FDA, however, have historically considered CIS to be its own separate entity. That makes this decision doubly surprising, according to Fox, since the EXPAND trial only enrolled patients with SPMS, not CIS.   “It's the first time I've seen them approve for CIS specifically when there wasn't a trial in CIS,” Fox said. “I agree with it — I don't have a problem with it — it just surprised me that the regulators were so progressive in their appreciation of MS.” The second — and far more unsettling — surprise was the FDA’s decision to only approve Mayzent for “active” SPMS patients, instead of all SPMS patients. This decision didn’t come out of nowhere, he noted, but it remains puzzling in the context of the EXPAND trial.  In compiling trial results, investigators did a subgroup analysis — as they often do, almost as an aside for research reasons — and found more favorable responses to Mayzent treatment in patients with active inflammation before the trial's start, those it determined to be with "active" disease.   “There was a third of patients who had a relapse in the two years prior to enrollment, and those patients actually had a 30% slowing in disability progression, compared to the 21% overall,” Fox said. This certainly does suggest that Mayzent can be more effective in people with active disease — but there's a catch. The trial itself was not designed to make such a distinction. It enrolled SPMS patients regardless of activity, and its priority goal was changes in disease progression across all who were treated with Mayzent or given a placebo.   “What's important is that the trial was powered for the overall outcome. It was not powered for subgroup analysis,” Fox said, considering this a crucial point.  In clinical studies, being “powered” refers to the enrolling of whatever specific number of participants a study needs to ensure its results will reach statistical significance. More people are redundant and, as such, an unnecessary cost; fewer could mean that trial's conclusions cannot be supported by rigorous scientific measures.  In other words, Fox said, the only conclusions that can be drawn from the EXPAND study reliably — with rigor — are based on data drawn from all its SPMS patients, not a subgroup with active disease. This trial “followed over 1,600 patients for the clinical disability. These are purposely powered so that you're not following twice as many people as you need to … you're powered for that primary outcome,” he said. “So, how could they [the FDA] look at a subgroup analysis and make an approval decision based on a subgroup analysis that was underpowered?” The neurologist gave as examples other subgroup differences found in trial analyses that didn't affect regulatory approval — but to his mind, equally could have. One was an analysis finding female SPMS patients responded to the therapy better than males, showing lesser disease progression. "So why didn't they just approve it for the females and not the males?" Fox asked. But, when asked, Fox did not think the label to necessarily be an error. "My point is the absurdity of it," he said. "How could they make the regulatory approval based on a subgroup analysis that wasn't powered for conclusions?" He was also particularly troubled because the FDA “didn't define what ‘active’ means — is it just a relapse, or is it MRI disease activity?"  For many clinicians, “active” SPMS refers to ongoing inflammation that can be observed on MRI (magnetic resonance imaging) scans. In EXPAND, however, the active subgroup was defined as patients with clinical relapses within two years of being enrolled in the trial. Fox worries about this apparent lack of a regulatory definition of "active" SPMS, since “obviously, the insurance companies are going to seize upon that, and they're going to look for every way they can to avoid covering it for patients.” Mayzent, Fox agreed, is likely to be expensive. The therapy is reported to carry a U.S. list price of $88,500 a year. “I always have a concern about the cost of these drugs. They're all fearfully expensive,” he said, noting he treats SPMS patients. His focus now is on working to ensure that possible regulatory and financial hurdles won’t pose too much of an obstacle for patients, especially those with SPMS. “I don't know what the insurance companies are going to do with this, but I'm hoping that it is available for my patients, and I say that as their clinician,” Fox concluded.

April 2, 2019 News by Joana Carvalho, PhD

NeurologyLive Launches Series of Educational Videos About MS

NeurologyLive has launched a series of educational videos intended to provide an overview of the diagnositic methods and treatment options available to multiple sclerosis (MS) patients. The video series, “Advances in the Diagnosis and Management of Multiple Sclerosis,” also will include future perspectives on upcoming MS therapies,…

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