July 3, 2019 News by Ana Pena PhD

NervGen to Advance NVG-291 as Potential Remyelination Therapy for MS

NervGen wants to advance the development of NVG-291, its lead investigational therapy for spinal cord damage, as a potential remyelination treatment for multiple sclerosis (MS), the company announced. Following preclinical data showing that NVG-291 promotes myelin repair and regeneration of damaged nerves in animal models of…

July 2, 2019 News by Jose Marques Lopes, PhD

Protein Linked to Microglia Cell Activation and Nerve Fiber Damage in Study That Also Notes Potential Treatment

A protein leads to nerve fiber and myelin damage, particularly in progressive forms of multiple sclerosis, by activating brain immune cells called microglia, according to a new study. Its researchers also noted this protein is the target of experimental MS treatment called temelimab (GNbAC1), which showed potential in Phase 2 clinical trials. The…

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.

February 22, 2019 News by Iqra Mumal, MSc

New Compounds Offer Significant Anti-inflammatory, Neuroprotective Benefits in MS Mouse Study

Two newly identified variants of the known pharmaceutical agent chloroindazole showed significant anti-inflammatory and neuroprotective benefits in a mouse model of multiple sclerosis, a new study shows. Multiple sclerosis is an autoimmune, demyelinating disease of the central nervous system with no known cause or cure. Patients with MS characteristically show loss of the myelin sheath, a protective coat in nerve cells that helps increase cell-to-cell signaling. Several studies have suggested that estrogens — a type of hormone — are beneficial to the functioning of the central nervous system, and help regulate the immune system. Thus, they are attractive candidates for the treatment of MS. However, despite their potential to treat MS, estrogen-based therapies can have several undesirable side effects, such as feminizing male recipients and increasing the risk of developing breast and endometrial cancers in females. Interestingly, estrogens work by binding and activating two different types of receptors: the estrogen receptor (ER)α and ERβ. The cancer-inducing effects of estrogens are mediated mainly through estrogen receptor ERα. Hence, therapies that specifically target ERβ can bypass these deleterious effects. Chloroindazole (IndCl), a pharmaceutical agent, has up to 100-fold relative binding affinity for ERβ over ERα. IndCl has been shown previously to have beneficial effects on modulating the immune system and the central nervous system, and inducing myelination of nerve cells in mouse models of MS. Furthermore, IndCl and other ERβ-activating agents directly support the growth, differentiation (maturation), and overall myelination activity of oligodendrocytes, which are the nerve cells that produce the myelin sheath. Therefore, in order to optimize the benefits of IndCl, researchers developed and screened seven novel IndCl analogues for their ability to promote oligodendrocyte survival, growth, and differentiation. These analogues have a molecular structure closely similar to that of IndCl, but interact with estrogen receptors in subtly different ways. Among these seven compounds, researchers found two analogues — IndCl-o-chloro and IndCl-o-methyl — that stimulated growth and differentiation similar to the original IndCl. Next, researchers evaluated the benefits of these compounds in a mouse model of MS — the experimental autoimmune encephalomyelitis (EAE) mouse model — to determine whether they could alter the disease course, white matter pathology (level of demyelination), and inflammation. Results indicated that both compounds “ameliorated disease severity, increased mature OLs [oligodendrocytes], and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord,” researchers wrote. Corpus callosum is a thick band of nerves that connect the left and right side of the brain. White matter tracts connect the cortex (the largest part of the brain) with other areas in the central nervous system. These beneficial effects were accompanied by a reduced production of the toxic, inflammatory molecules interferon-γ and CXCL10. Additionally, IndCl-o-methyl also reduced the levels of peripheral interleukin (IL)-17, a molecule that strongly induces inflammation. Furthermore, IndCl and both analogues upregulated the expression of a compound called CXCL1, which is associated with increased production of oligodendrocytes. Not only were these two newly identified compounds equivalent to IndCl, but the two analogues performed better in reducing disability and encouraging remyelination than the original compound, and without any obvious side effects. “The o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection, as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases,” the researchers concluded. “We believe we created a drug that does two things really well, modulating inflammation and allowing axon remyelination. No other drug on the market can do these two things simultaneously,” Seema K. Tiwari-Woodruff, said in a press release written by Stacy Kish. Tiwari-Woodruff is the study's lead author. “The most amazing part of the study is that these new analogues of a known estrogen modulator, chloroindazole, are superior in treating mouse model of multiple sclerosis,” she added. The team has patented the analogues, and hopes to begin further pharmacological and toxicity studies soon.

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 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 2, 2019 News by Jose Marques Lopes, PhD

Top 10 Multiple Sclerosis Stories of 2018

Multiple Sclerosis News Today brought you daily coverage of key findings, treatment developments, and clinical trials related to multiple sclerosis (MS) throughout 2018. We look forward to reporting more news to patients, family members, and caregivers dealing with MS during 2019. Here are the top 10 most-read articles of…

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