Jonathan Grinstein,  —

Articles by Jonathan Grinstein

January 28, 2019 News by Jonathan Grinstein

Altered Oligodendrocyte Diversity Contributes to Multiple Sclerosis, Study Suggests

Subpopulations of oligodendrocytes — cells that produce the myelin sheath that protects nerve fibers — are altered in patients with multiple sclerosis, a study shows. These findings suggest that oligodendrocyte diversity and the different functions of these subpopulations might have a greater role in the disease than previously thought. The severity of MS varies greatly, and the patient's disability level does not correlate well with the degree of myelin loss. This suggests that other factors contribute to MS severity. One such factor may be that oligodendrocytes are heterogeneous — diverse in makeup and function. For example, oligodendrocytes in mouse spinal cords are known to naturally produce longer myelin sheaths than oligodendrocytes in the mouse brain. Additionally, individual oligodendrocytes have been shown to have different molecular makeups. However, the extent of human oligodendrocyte diversity and its possible contribution to MS pathology remains unknown. Researchers from the Karolinska Institutet and the MRC Centre for Regenerative Medicine studied the differences of individual human oligodendrocytes from healthy and MS brains to assess their diversity. Specifically, the team examined oligodendrocytes from the white matter areas of post-mortem human brains both from MS and non-MS patients. The team examined the RNA content — the messenger molecule carrying instructions from DNA for the production of proteins — from individual oligodendrocytes. Researchers identified groups of RNA molecules that defined features of oligodendrocytes from healthy human white matter. Some of these groups match those that defined oligodendrocytes in healthy mice. Strikingly, some of these RNA molecules in healthy brains were under-represented in oligodendrocytes from MS brains, whereas others were more prevalent. “We found that oligodendrocytes are a diverse population of cells and that different types are likely to have different functions in the brain,” Charles ffrench-Constant, the study's co-lead author, said in a Karolinska Institutet news release written by Katarina Sternudd. These differences in oligodendrocyte RNA content may indicate different functional states of oligodendrocytes in MS lesions. “The proportions of different resident oligodendrocytes in the lesions are changed, along with their properties, suggesting that they might have important roles in MS,” said Eneritz Agirre, PhD, a study co-author. Furthermore, the researchers believe that this altered diversity in oligodendrocytes in MS may be important to understand disease progression and develop therapeutic approaches. “Understanding which types of oligodendrocytes are most beneficial in repairing myelin will be crucial for maximizing the chances of developing much-needed treatments for MS,” said Anna Williams, PhD, study co-lead author. The team concluded that the changes in different oligodendrocyte subpopulations in MS suggest "a more complex role of these cells in the pathology of the disease, but also in regeneration of new cells,” said Gonçalo Castelo-Branco, PhD, another study co-lead author.

January 24, 2019 News by Jonathan Grinstein

New Products Intended to Stimulate Feet of MS Patients

Naboso Technology has expanded its product offerings with new insoles and training mats specifically designed to stimulate the nervous system through the skin on the bottom of the feet. The products were developed to help improve balance, posture, movement and restore motor function, as part of a neurorehabilitation strategy…

January 21, 2019 News by Jonathan Grinstein

Fatigue More Common in Progressive MS Patients, Survey Shows

Fatigue is more prevalent among patients with progressive multiple sclerosis (MS), according to a study that surveyed patients on fatigue and factors related to it. In addition, increased fatigue severity correlated with greater physical, cognitive, and psychological impairment, although the strength of this link was largely the same…

January 18, 2019 News by Jonathan Grinstein

Small Molecule Shows Ability to Limit Autoimmune Response in MS, Mouse Study Reports

A small molecule called Sephin1 may be able to significantly delay harm to neurons in multiple sclerosis (MS) by protecting oligodendrocytes, limiting the autoimmune response, a mouse study reports. The study, “Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis,” was published in the journal Brain. MS is thought to be caused by immune-mediated inflammation that damages the myelin — an insulating sheath around nerve cells. For this reason, current MS disease-modifying treatments focus on immune-mediated inflammation. Although these treatments moderate disease relapses, their impact on disease progression is unclear. Previous studies have demonstrated that oligodendrocytes — cells that produce myelin — are critical in protecting against neuron demyelination and axon (nerve fiber) damage. As a result, researchers have been keen to develop alternative therapeutic approaches that protect oligodendrocytes, and ultimately limit disease progression.  A signaling pathway called integrated stress response that acts as a natural defense system to protect cells has been shown to reduce the inflammatory impact on oligodendrocytes. This response is triggered by phosphorylation (a chemical reaction) of a protein called eukaryotic initiation factor 2 alpha (eIF2α), and reduces the total production of proteins, instead promoting the synthesis of protective proteins in the cells. Conversely, the integrated stress response can be cut off by dephosphorylation of eIF2α. Sephin1 was shown to inhibit the dephosphorylation of eIF2α, prolonging the protective response. In this study, researchers at the University of Chicago proposed that Sephin1, by producing this response, could protect oligodendrocytes and slow the progress of the disease. The team tested their hypothesis in a mouse model called experimental autoimmune encephalomyelitis (EAE), which is similar to MS in humans. Results showed that treatment with Sephin1 did inhibit eIF2α dephosphorylation in EAE mice, triggering a protective response against inflammation. More importantly, myelin-producing oligodendrocytes were also protected, and disease onset was significantly delayed. This correlated with diminished oligodendrocyte loss, protected neuronal axons and myelin, and prolonged integrated stress response. In addition, Sephin1 decreased the levels of inflammatory immune T-cells, and the production of inflammatory signals within the central nervous system. "By protecting oligodendrocytes and diminishing demyelination, we also reduce the generation of myelin debris,"  Brian Popko, PhD, the study's senior author, said in a press release. "The decreased exposure to myelin fragments should also limit the auto-immune response." Popko is the Jack Miller professor of neurological disorders, and director of the Center for Peripheral Neuropathy at the University of Chicago. The effects of Sephin1 were also combined with interferon-beta treatment — an anti-inflammatory first-line MS therapy. Researchers found that the combination was more effective than the therapies given separately. "Encouragingly, adding Sephin1 to the established anti-inflammatory MS drug interferon beta provided additive benefits to the mouse MS model," said study co-author Yanan Chen, PhD, a postdoctoral fellow in the Popko laboratory. The team concluded that the results "suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients." Treatment with Sephin1, they say, "could lead to a better clinical outcome in multiple sclerosis patients as a safe neuroprotective drug, perhaps when used in combination with immune-modulatory therapies." Sephin1 has been patented and licensed to InFlectis BioScience, a French biotech company.

January 14, 2019 News by Jonathan Grinstein

Tecfidera Effective in East Asian RRMS Patients, Phase 3 Trial Shows

Tecfidera (dimethyl fumarate) demonstrated strong efficacy in Japanese and other East Asian patients with relapsing-remitting multiple sclerosis (RRMS), a Phase 3 clinical trial shows. These results are consistent with previous clinical trials, which included mostly white MS patients, and show that Tecfidera can also be effective across various other patient demographics. Findings of the trial were reported in the study, “A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries,” in the journal BMC Neurology. Tecfidera, a delayed-release dimethyl fumarate capsule, marketed by Biogen, is an oral therapy approved in many parts of the world for the treatment of RRMS. In previous Phase 3 clinical studies, DEFINE (NCT00420212), and CONFIRM (NCT00451451), Tecfidera showed substantial effectiveness on clinical and neuroradiological measures in RRMS patients. The study participants were predominantly white (79% in DEFINE and 84% in CONFIRM), and there were 10% or fewer East Asian patients. In general, very little data is available on Tecfidera's effectiveness in East Asian MS patients. In this APEX Part 1 (NCT01838668) trial, researchers from the Kansai Medical University in Japan and Biogen evaluated the safety and efficacy of Tecfidera over 24 weeks (six months) in the treatment of RRMS patients from East Asia and other countries. Participants with active MS between the ages of 18 and 55, with ethnic origins in Japan, South Korea, or Taiwan were included. To compare East Asian and white MS patients, study enrollment was expanded to patients from Eastern Europe (Czech Republic and Poland). In all, the six-month, double-blind, placebo-controlled study recruited 225 patients, 142 of whom were East Asian (63.4%). It was completed by 213 participants. Patients were randomly assigned to receive Tecfidera, (240 mg, twice daily) or a matching placebo for six months. They were assessed at the beginning of the study, at three months, and again at six months. They underwent MRI (magnetic resonance imaging) scans for neurological examination, in addition to routine health checks. The primary objective of the study was the total number of new inflammatory lesions on brain MRI scans from three to six months. Secondary goals included the number of specific new, or newly enlarging T2 hyperintense lesions — lesions reflective of damage to nerve cell connections — from the beginning of the study to six months. Tertiary goals included standard safety measurements, and annualized relapse rate over six months. “We chose radiological measures to serve as primary and secondary endpoints, due to the ability of MRI to detect lesions that might not produce clinical manifestations in the short-term,” the researchers wrote. Results showed that Tecfidera treatment significantly reduced (84%) the total number of new MRI lesions from weeks 12 to 24 (primary objective), compared with placebo — specifically by 85% in the Japanese subgroup, 81% in the total East Asian subgroup, and 87% in the Eastern European subgroup. Regarding the trial's secondary objective, the total number of new MRI lesions from the beginning of the study up to six months was reduced by 75% in the Tecfidera group (78% in the Japanese, 76% in the East Asian, and 73% in the Eastern European subgroups), and the mean number of new/newly enlarging T2 hyperintense lesions was reduced by 63% in the Japanese, and 58% in the East Asian subgroups, compared with placebo. Most patients reported one or more adverse events (77% in the placebo group and 86% in the Tecfidera group). Most adverse events were mild or moderate in severity, and the ones affecting patients taking Tecfidera either related mainly to flushing symptoms or to gastrointestinal problems. The team concluded that the "results suggest that the strong efficacy and favorable benefit-risk profile of [Tecfidera] extends to Japanese and other East Asian patients with MS." The second part of the ongoing clinical trial, APEX Part 2, is an open-label extension trial — where both the researchers and participants know which treatment they are getting — designed to further examine the long-term safety and tolerability of Tecfidera in East Asian MS patients.

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