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August 1, 2018 News by Diogo Pinto

Pregnancy Worsens Symptoms in MS Patients, Study Finds

Pregnancy, including successful delivery or miscarriage, worsens symptoms of multiple sclerosis (MS), as well as onset of the disease, a retrospective study shows. Researchers found the same effect of pregnancy on neuromyelitis optica spectrum disorders (NMOSD), an inflammatory disorder of the central nervous system characterized by demyelination and damage of…

July 31, 2018 News by Joana Carvalho, PhD

Researchers Succeed at Generating Oligodendrocytes, Key to Myelin Renewal, in Tissue Created in Lab

Researchers at Case Western Reserve University School of Medicine have developed a cutting-edge laboratory technique able to turn human stem cells – special cells able to grow into any type of cell in the body – into brain-like tissues in a culture dish. They intend to use their tool to study how myelination – the deposition of myelin around nerve cells – occurs in the central nervous system, and how diseases such as multiple sclerosis (MS) impair this process. The experimental protocol to grow these structures outside an organis) is described in the study, "Induction of myelinating oligodendrocytes in human cortical spheroids," published in the journal Nature Methods. These structures, called “oligocortical spheroids,” are small spheres that contain all the major cell types usually found in the human brain, including oligodendrocytes — cells that produce myelin, which is the fatty substance that insulates nerve fibers. Previous cerebral organoid techniques failed to include oligodendrocytes. “We have taken the organoid system and added the third major cell type in the central nervous system — oligodendrocytes — and now have a more accurate representation of cellular interactions that occur during human brain development,” Paul Tesar, PhD, associate professor of genetics and genome sciences at Case Western's medical school and the study's senior author, said in a press release. Oligodendrocytes are essential to good brain health. Without these cells, myelin production is hampered and nerve cells cannot communicate effectively, and eventually they start to deteriorate. This is the starting point for many neurological disorders caused by myelin defects, including MS and rare pediatric genetic disorders like Gaucher disease. Using this new organoid system and these myelin-producing cells, researchers intend to study the process of myelination — how it occurs in normal circumstances and how neurodegenerative diseases disrupt this process. “This is a powerful platform to understand human development and neurological disease,” Tesar said. “Using stem cell technology we can generate nearly unlimited quantities of human brain-like tissue in the lab. Our method creates a ‘mini-cortex,’ containing neurons, astrocytes, and now oligodendrocytes producing myelin. This is a major step toward unlocking stages of human brain development that previously were inaccessible.” Researchers not only demonstrated that they were capable of generating mature oligodendrocytes derived from human stem cells in vitro, but they also showed these cells were able to exert their function and produce myelin starting at week 20 in a culture dish. Their improved organoid system could also be used to test the effectiveness of potential myelin-enhancing treatments. “These organoids provide a way to predict the safety and efficacy of new myelin therapeutics on human brain-like tissue in the laboratory prior to clinical testing in humans,” said Mayur Madhavan, PhD, co-first author on the study. To prove this point, researchers treated organoids with promyelinating compounds known to enhance myelin production in mice, and measured the rate and extent of oligodendrocyte generation and myelination. Under normal conditions, adding promyelinating drugs to cultured organoids increased the rate and extent of oligodendrocyte generation and myelin production, the team reported. But results differed in important ways using diseased organoids.  Specifically, treating organoids generated from patients with Pelizaeus-Merzbacher disease — a fatal genetic myelin disorder — brought an in vitro recapitulation of the patients' symptoms. “Pelizaeus-Merzbacher disease has been a complicated disorder to study due to the many different mutations that can cause it and the inaccessibility of patient brain tissue,” said Zachary Nevin, PhD, co-first author on the study. “But these new organoids allow us to directly study brain-like tissue from many patients simultaneously and test potential therapies.” Altogether, these findings demonstrate that oligocortical spheroids could be a versatile in vitro system to study how myelination occurs in the central nervous system, and a possible model for testing new therapies for neurodegenerative disorders. “Our method enables generation of human brain tissue in the laboratory from any patient,” Tesar said. “More broadly, it can accurately recapitulate how the human nervous system is built and identify what goes wrong in certain neurological conditions.”

July 30, 2018 News by Jose Marques Lopes, PhD

African-Americans Show Better Adherence and Satisfaction with Gilenya Than Injectable DMTs, Phase 4 Study Finds

African-Americans with relapsing–remitting multiple sclerosis (RRMS) show higher adherence and greater satisfaction when treated with oral Gilenya (fingolimod, by Novartis) than with injectable therapies, according to a new study. The research, “Treatment retention on fingolimod compared with injectable multiple sclerosis therapies in African-American patients: A…

July 27, 2018 News by Joana Carvalho, PhD

Cladribine Added to Interferon-beta Seen to Lower Relapses in Active MS, But Safety Questioned

Cladribine tablets added to interferon-beta treatment significantly reduced the probability of relapses over 96 weeks in people with active relapsing multiple sclerosis , a Phase 2 clinical trial found. But a troubling diminishment in key immune cells was also seen in treated patients. Relapsing-remitting MS is marked by periods of flares caused by inflammatory attacks, followed by periods of partial or complete recovery . A majority --about 65 percent -- go on to develop secondary progressive MS. Despite the growing number of treatment options — including disease-modifying therapies — for these MS patients, efforts continue into better ways to lower relapse frequency and slow disease progression. Researchers tested the safety and efficacy of cladribine tablets as an add-on therapy in patients continuing to experience active relapses while under interferon-beta treatment. Cladribine is an oral medication that works by selectively targeting and reducing the number of immune cells involved in the inflammatory attacks occurring in active MS. It was developed by EMD Serono (Merck KGaA outside the U.S. and Canada) and approved in the European Union using the brand name Mavenclad (it is not approved in the U.S. for MS). Interferon-beta works by balancing pro- and anti-inflammatory signals, reducing the number of immune cells and promoting the survival of nerve cells. Interferon-beta therapies are marketed under several brand names; in the study, researchers analyzed patients using Rebif (marketed by EMD Serono), Avonex (by Biogen), and Betaseron/Betaferon (by Bayer). The 96-week, randomized, double-blind, Phase 2b trial called ONWARD enrolled a total of 172 patients with active relapsing MS, who were randomly divided into two groups: those given cladribine tablets together with interferon-beta, and those that received a placebo and interferon-beta. Results showed those taking cladribine tablets together with interferon-beta had 63% lower likelihood of a relapse compared to those given an add-on placebo. Add-on cladribine treatment also reduced most measures of disease activity as assessed by magnetic resonance imaging (MRI) — namely, the number of new brain and spinal cord lesions. However, almost half of patients in this treatment group developed lymphopenia, a condition where the levels of lymphocytes (important immune white blood cells) in the blood are abnormally low. None in the control group developed the condition. Other reported side effects, including other serious adverse side effects, were identical in the two groups. Altogether, the findings indicate that a cladribine and interferon-beta combination can successfully lower the probability of relapses over the course of 96 weeks, but also increase a person's chances of lymphopenia.

July 25, 2018 News by Jose Marques Lopes, PhD

Immune Response Promotes Remyelination in MS Mouse Model

Activation of the immune response mediated by cells called microglia favors remyelination and myelin repair in multiple sclerosis (MS), according to a new Canadian study using mice. The research, “mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis,” was…

July 23, 2018 News by Ana Pena PhD

Shorter Washout Period Lessens Relapse Risk When Switching from Tysabri to Gilenya in RRMS, Study Finds

Shortening the washout period to four weeks when switching from Biogen’s Tysabri to Novartis’ Gilenya is safe and reduces the chances of experiencing a disease flare in patients with relapsing-remitting multiple sclerosis (RRMS), a small Swiss study found. A four-week washout reduced the risk of having a disease relapse or an increase in disease activity, compared with an eight-week washout period, for two years after switching from Tysabri to Gilenya. Although Tysabri effectively slows worsening of MS symptoms and the appearance of disease flares, its use is under a strict risk management plan as it heightens the risk of developing a rare and life-threatening brain infection called progressive multifocal leukoencephalopathy, also known as PML. Some patients may switch to Gilenya, an alternative disease-modifying therapy for RRMS. Gilenya has been associated with a lower risk of PML infection and seen to reduce relapses, disability worsening, and the appearance of new brain lesions on clinical trials. It also is the only therapy approved by the U.S. Food and Drug Administration for children with MS as young as 10. When switching from Tysabri to Gilenya, it is important to consider the washout period, which is the period when the patient is taken off medications. If too long, it may lead to disease reactivation, which can be even stronger than before starting Tysabri. There is little evidence about the optimal length of washout periods, but a Phase 3 trial showed that an eight-week washout between Tysabri and Gilenya was beneficial compared with longer washouts of 12 or 16 weeks. The eight-week washout enabled more RRMS patients to become free from relapses and lowered disease activity. To study if a shorter washout period of four weeks further reduced the risk of MS reactivation, researchers conducted an open-label, observational study at the University Hospital, Basel, Switzerland. The study enrolled 25 RRMS patients who were appointed to switch from Tysabri to Gilenya. Participants were assigned to either a four-week or an eight-week washout period, and were followed for two years after switching to Gilenya. Although patients were older in the four-week washout group, disease activity and disability scoreswere not significantly different between groups at the beginning of the study. Relapses, disability scores, and disease activity on magnetic resonance imaging scans were recorded at baseline and weeks 8, 12, 16, 20 32, 56, and 108. In the first year (week 56) the proportion of patients with disease flare-ups or disease activity on MRI was not significantly different between the two washout groups, affecting 55.6% and 62.5% of the patients who had a four-week and an eight-week washout, respectively. However, at the end of the two-year follow-up (week 108), recurrent event analysis showed that patients who were on the four-week washout group were 77% less likely to experience relapses. The combined risk for relapse or disease activity on MRI also was 58% lower in the four-week group, compared with those who had an eight-week washout. In addition, researchers found that patients who had flares more frequently in the year before discontinuing Tysabri also had a nearly four times higher risk of experiencing relapses in the first year after switching to Gilenya. This suggests that the number of relapses before switching from Tysabri can predict disease reactivation once on other disease-modifying therapies. Both washout periods were deemed safe, with no serious adverse side effects or cases of opportunistic infections, including PML, being reported. Researchers emphasized, however, that the findings need to be confirmed in larger studies.

July 20, 2018 News by Iqra Mumal, MSc

Tysabri Treatment Lessens Sexual Dysfunction in MS Patients, Study Finds

Treatment with Tysabri (natalizumab) can help lessen sexual dysfunction in patients with multiple sclerosis (MS), a new study shows. The study, “Patient perceived changes in sexual dysfunction after initiation of natalizumab for multiple sclerosis,” was published in the Multiple Sclerosis Journal – Experimental, Translational and Clinical. MS is…

July 20, 2018 News by Patricia Inacio, PhD

Single Gene Variant May Identify MS Patients at Risk of Liver Damage Linked to Interferon-Beta Use, Study Says

A genetic variant close to a gene called interferon regulatory factor 6 (IRF6) may help to predict those multiple sclerosis (MS) patients most at risk of liver injury while using interferon-beta therapies, a study reports. The study, “Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis” was published…

July 18, 2018 News by Iqra Mumal, MSc

Non-fermentable Fiber Diet Helped Prevent MS in Mice

A diet that incorporates non-fermentable fiber — a common component of a vegetarian diet — during early life can help prevent the onset of autoimmune diseases such as multiple sclerosis (MS), a new study shows. The study, “Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and…

July 17, 2018 News by Alice Melão, MSc

Progressive MS Patients with Considerable Disability Ably Treated with Cladribine, UK Case Study Reports

Cladridine may be effective in preventing disability progression and reducing damage to nerve cells in people with progressive forms of multiple sclerosis (MS), researchers suggest based on a case study of two such patients given the injectable treatment. MS is characterized by progressive degeneration of cells in the central nervous system, mostly…

July 12, 2018 News by Ana Pena PhD

Missouri Trial to Examine if Fasting Alters Gut Microbiome and Immune System of RRMS Patients in Helpful Ways

A 12-week clinical study is recruiting people with relapsing-remitting multiple sclerosis (RRMS) to evaluate if intermittent fasting can improve their immune response, metabolism, and gut microbiome — the bacterial community that inhabits the gastrointestinal tract. Its findings may also hint at whether such a diet might ease MS symptoms or alter discourse course and, if used in conjunction with other treatments, boost their efficacy. Conducted by researchers at Washington University in St. Louis, Missouri, the trial is supported by their findings in an earlier mouse study.  Results showed that fasting worked to ease MS-like symptoms in a mouse model of the disease, the research team reported. Specifically, EAE mice fed every other day were less prone to symptoms that included difficulty in walking, limb weakness, and paralysis than mice allowed to eat freely.  A fasting diet also enriched bacterial diversity in the mice guts, and shifted immune cell populations there toward a lower inflammatory response. When gut bacteria were transferred from fasting mice to nonfasting mice, the later also were seen to be better protected against MS-like movement problems, supporting the influence of the gut microbiome on MS symptoms. Several diets have been proposed to help ease disease progression in MS patients, but solid scientific evidence is lacking to support any one diet over another, leaving the issue much to an individual’s choice. “The fact is that diet may indeed help with MS symptoms, but the studies haven’t been done,” Laura Piccio, MD, an associate professor of neurology at WUSTL and the study's lead author, said in a WUSTL news release written by Tamara Bhandari. Taking place at the Missouri university, the trial is expected to enroll 60 RRMS patients. Half will be randomly assigned to eat a standard Western-style diet seven days a week, and the other half to Western-style diet five days a week, with two days set aside for fasting (consuming a maximum of 500 calories each day). On fasting days, patients can only drink water or calorie-free beverages and eat fresh, steamed or roasted non-starchy vegetables All will undergo a neurological assessment, and provide blood and stool samples in the study's beginning, at mid-point or week six, and at its end (week 12). Those using MS medications will continue on their prescribed treatment regimens throughout the study. More information, including enrollment information, is available here. Piccio noted that a pilot study on diet in 16 MS patients showed that limiting calories every other day for two weeks led to immune and gut microbiome changes that resembled those observed in the mice study she helped to lead. Its researchers concluded that intermittent fasting had the potential to positively manipulate the immune response in MS patients by changing their gut microbiome. The gut microbiome plays a central role in digestion, and in producing vitamins and amino acids (the building blocks of proteins). But a growing body of evidence indicates that it also determines how our immune systems develops and matures. Indeed, an increasing number of studies link irregularities in the gut microbiome with MS. “There are several possible ways fasting can affect inflammation and the immune response,” Piccio said. “One is by changing hormone levels. We found that levels of the anti-inflammatory hormone corticosterone were nearly twice as high in the fasting mice. But it also could act through the gut microbiome.” The new trial will allow the team to analyze more deeply the effects of a fasting diet — and perhaps gather evidence for a larger study investigating if skipping meals can ease MS symptoms. Its goal is to find out "whether people on limited fasts undergo changes to their metabolism, immune response and microbiome similar to what we see in the mouse,” Piccio said. “I don’t think any physician working with this disease thinks you can cure MS with diet alone,” she added, “but we may be able to use it as an add-on to current treatments to help people feel better.”

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