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ECTRIMS Congress

Access daily, concise peer-reviewed reports from the Congress of ECTRIMS selected by the Neurology Today editors.

Sunday, September 13, 2020

Modulating a type of microRNA that is involved with macrophage function—promoting tissue repair and regeneration in multiple sclerosis (MS) in the process—is possible with an oligonucleotide packaged in a nanoparticle carrier, researchers said in a session at MS Virtual 2020, the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.

The approach, they said, could act as a kind of rudder that could steer macrophages' effects once they infiltrate peripheral immune cells. In MS, macrophages are either in the pro-inflammatory or M1 state or a state with a key role in tissue repair and regeneration, the M2 state.

"MiR-15 inhibition can be achieved through delivery of an anti-mRNA oligonucleotide [AMO]," said Frances K. Nally, a second-year PhD candidate at the RCSI University of Medicine and Health Sciences in Ireland.

Researchers previously found that inhibition of miR-155 by interleukin-10 is an important mechanism for macrophages to stay in the repair and regeneration state. A model in which miR-155 was deleted from myeloid cells brought about reduced disease onset and a lower burden of disease in an animal model of experimental autoimmune encephalomyelitis.

They proposed that like the mediating effect of IL-10, inhibition of miR-155 could potentially modulate the macrophage population to an 'M2' or pro-repair phenotype, reducing inflammation and alleviating disease progression.

Researchers investigated four anti-miRNA oligonucleotides for their ability to inhibit miR-155 in raw murine macrophage cells and bone marrow-derived macrophages. They looked at the downstream effect of macrophages' pro-inflammatory function in response to miR-155 inhibition by looking at pro-inflammatory cytokine production and M2 state markers.

Locked nucleic acid-modified anti-mRNA oligonucleotides performed the best for inhibiting miR-155 in the macrophage samples. In these structures, a "bridge" of methylene connects two atoms, resulting in a more rigid formation, Nally explained.

In further studies, the researchers said, they saw changes in the expression of miR-155 target genes that were similar to the phenotype seen with IL-10 mediation.

Nally acknowledged that effects seen in a dish are one thing, but that it is a "very different problem when trying to bring this in vivo."

A star-shaped polypeptide, Nally said, holds promise for being a delivery vehicle for the AMO, she said. Researchers found they are well-tolerated in bone marrow-derived macrophages.

"Future work will test these Star-AMO-155 polyplexes as a delivery system in vivo," she said.

In a question-and-answer discussion, session moderator Thomas Korn, MD, professor of experimental neuroimmunology at the Technical University of Munich, raised questions about the approach that might be worth exploring further. He said that while the data showed an increase in arginase 1, a marker of the anti-inflammatory macrophage state, there was also a strong drop off in inducible nitric oxide synthase (iNOS), which is a key player in the macrophage inflammatory response.

"Is this an indirect effect?" Dr. Korn asked. "How do you explain this? Is this because the macrophages change the phenotype, and then you have less iNOS expression?"

Nally said her team proposes that it is more an indirect effect of miR-155 on transcription factors, but they haven't deeply explored that question yet. She added that much more research will be needed to explore the therapeutic potential of this approach.

Nally and Dr. Korn had no relevant disclosures.

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MS Virtual 2020 Abstract PS02.05: Nally F, Lyons V, De Santi C, et al. Nanomodulation of microRNAs in macrophages.

Nally FK, De Santi C, McCoy CE. Nanomodulation of macrophages in multiple sclerosis.Cells 2019;8(6):543.

Sunday, September 13, 2020

B cell-derived interleukin-10 (IL-10) can help diminish inflammatory responses of microglia and astrocytes in the central nervous system, researchers said here at MS Virtual 2020, a joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.

The findings help clarify the role of B cells in multiple sclerosis (MS), they said.

"Regulatory B cell function may be important in controlling central nervous system-intrinsic inflammation associated with clinical progression," Darius Hausler, PhD, a research fellow at the Medical University of Gottingen, said in his virtual presentation.

Several lines of research suggest that B cells play critical roles in the pathogenesis of MS, acting as potent antigen-presenting cells. Through the course of chronic MS, structures that are B cell follicle-like are found in the meninges of MS patients. Still, how B cells interact with central nervous system cells—in fact, whether they do at all—has not been clear, the researchers said.

In this study, primary microglia and astrocytes were produced from newborn mice and incubated with activated B cells or the supernatants of the cells. IL-6 and IL-10 production was abolished through genetic means or was neutralized with the use of antibodies. Then the central nervous system cells were co-cultured with T cells specific to myelin oligodendrocyte glycoprotein (MOG), Dr. Hausler said.

Researchers also depleted B cells in mice with anti-CD20 injections and then immunized them with MOG peptide p35-55, an environment in which B cells remain naïve. They then assessed the activation and modulation of microglia and astrocytes.

The IL-10 neutralization and deficiency brought about increased pro-inflammatory cytokine production, upregulation of co-stimulatory molecules, and more capacity to activate T cells as antigen-presenting cells, researchers said. The depletion of the naïve B cells worsened disease in mouse models of experimental encephalomyelitis (EAE) and boosted the number of immune cells that infiltrated the CNS.

"These findings highlight that B cells substantially alter the functional status of microglia and astrocytes in chronic CNS inflammation," researchers said. "Specifically, B cell-derived IL-10 is capable of diminishing the inflammatory responses of CNS-resident microglia and astrocytes. Our observation suggests that regulatory B cell function may be important in controlling CNS intrinsic inflammation associated with clinical progression."

Amit Bar-Or, MD, FRCPC, director of the Center for Neuroinflammation and Experimental Therapeutics at the University of Pennsylvania, said that while the study relies on data from mice, it touches on important themes. One point, he said, is that these findings show that while B cell depletion is effective at limiting new CNS inflammatory activity, "not all B cells are necessarily 'bad.'"

"Their results reinforce the view that the 'bad-guy' B cells in MS are within the memory B cell population, not the naïve B cell population," he said, "and that, in fact, amongst the naïve B cells, there may be regulatory B cells than can acquiesce CNS inflammation, providing a potentially new approach to MS and other auto-immune conditions."

Drs. Hausler and Amit-Or had no relevant disclosures.

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MS Virtual 2020 Abstract PS06.05: Gelaris A, Hausler D, Bruck W, Weber M. B cells regulate chronic CNS inflammation in an IL-10-dependent manner.

Arneth BM. Impact of B cells to the pathophysiology of multiple sclerosis. J Neuroinflammation 2019;16(1):128.

Sunday, September 13, 2020

A strong interaction between ozone pollution exposure and positivity for the HLA-DRB1*15 alleles boosts the risk of multiple sclerosis (MS) development in pediatric cohorts, researchers reported at the MS Virtual 2020 meeting, a joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.

Amin Ziaei, MD, PhD, a post-doctoral research fellow at the University of California, San Francisco, and colleagues wanted to assess the interaction between DRB1*15 status—the primary genetic variant linked with MS susceptibility—and ozone pollution.

"Our results suggest avoiding ozone exposure… as a lifestyle modification approach for MS," Dr. Ziaei said. The identification of a molecular mechanism underlying ozone exposure and increased MS risk may have potential implications for therapy in the future, he added.

However, he pointed out it is premature to conclude that clinicians need to test children for these alleles at this time.

In the study involving 355 cases and 565 controls who were enrolled by the US Network of Pediatric MS Centers, the odds of having pediatric MS increased with higher exposure to ozone, especially among those with the alleles,  Dr. Ziaei told Neurology Today At the Meetings.

Researchers used county-level data from the Centers for Disease Control and Prevention's Environmental Tracking Network air pollution database. The ozone values for subjects were based on their residence at the time of their enrollment in the study.

Researchers divided the exposure levels into tertiles and calculated an additive interaction between ozone and DRB1 of 2.74 for the tertile with the most ozone exposure, and 2.43 for the middle exposure group. They calculated that 60 percent of the disease measured among participants could be attributed to this additive interaction, Dr. Ziaei said.

Ozone exposure could be impacting MS risk in different ways, Dr. Ziaei said. It could have an effect on inflammation and oxidative insult in the CNS, modulating the immune system with an impact on the myelin sheath, Dr. Ziaei said. "This could cause CNS autoimmunity and CNS autoantigens," Dr. Ziaei said. "HLA-DRB1*15 alleles in immune cells have a high affinity to CNS autoantigens. That could cause this interaction between ozone exposure and HLA DRB-1."

Mitchell T. Wallin, MD, MPH, FAAN, associate professor of neurology at George Washington University and the University of Maryland, said the study is pursuing an important question but more details would be helpful.

"I agree with the premise that we have to understand what's going in the environment that can be driving MS. It's important to be looking at these factors," he said. "They found a risk, and I think it's important to point this out."

But the researchers did not report the length of exposure time. They grouped them by exposure level based on their county of residence at a particular time.

"I would think you would have to be exposed to this kind of pollutant for a certain amount of time before it's going to have an impact on your risk for developing MS," he said. "They probably need to do a little bit more work on time and amount of exposure within the cohort."

Drs. Ziaei and Wallin have no relevant disclosures.

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MS Virtual 2020 Abstract PS04.04: Ziaei A, Lavery A, Adams C, et al. Evidence for an interaction between ozone pollution and HLA-DRB1*15 alleles in pediatric multiple sclerosis.

Palacios N, Munger KL, Fitzgerald KC, et al. Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses. Environ Int 2017;109:64-72.

Saturday, September 12, 2020

The use of serum microRNA (miRNA) profiles together with MRI phenotypes may help characterize various pathological disease types in people with multiple sclerosis (MS), researchers suggested at MS Virtual 2020, the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.

MRI quantifies both the underlying neuroinflammation and accelerated brain atrophy in MS, the study authors noted in background material in the abstract; miRNA, which is implicated in different neurological disease processes, also have potential as biomarkers in MS.

In an attempt to classify and immunologically characterize people based on both MRI phenotypes and miRNA, the investigators retrospectively quantified brain parenchymal fraction and cerebral T2-hyperintense lesion volume from 1.5T MRI studies of a large cross-sectional group of 1,088 patients, and a subgroup of 153 individuals with at least five-years of longitudinal follow-up.

Based on that data, they defined the following MRI phenotypes: Type I: low T2 lesion volume, low atrophy; Type II: high T2 lesion volume, low atrophy; Type III: low T2 lesion volume, high atrophy; Type IV: high T2 lesion volume, high atrophy.

Each phenotype demonstrated a distinct miRNA signature, the researchers found.

 "MRI-defined MS phenotypes show high conversion rates characterized by relentless brain atrophy with or without ongoing inflammation, and results support the partial independence of these two features," reported Christopher C. Hemond, MD, assistant professor of neurology at the University of Massachusetts Medical Center in Worcester.

Serum miRNAs were assessed on a third MS cohort of 98 patients with two-year MRI phenotype stability, Dr. Hemond said. "Only type IV experienced significantly worse neurological disability scores," he reported.

 "Types I and II had a five-year MRI phenotype conversion rate of 33 percent and 46 percent, whereas Type III and Type  IV had greater than 90 percent stability," he reported. "Type II switched primarily to Type IV (91 percent); Type I switched primarily to Type II (47 percent) or Type III (37 percent)."

"Differentially expressed serum miRNA for the MRI phenotypes implicates the blood-brain barrier as an important mechanism for determining pathological course," Dr. Hemond suggested. "MicroRNA are promising as biomarkers in MS but require significant further verification and methodological standardization."

Commenting on the research, Robert J. Fox, MD, FAAN, vice chair for research at the Neurological Institute at the Cleveland Clinic in Ohio, said the focus on MRI phenotypes was interesting. "Many patients who have lots of lesions and little atrophy will eventually convert to lots of lesions and atrophy," he said, "but I don't think this has been characterized previously and deserves further focus."

On the other hand, Dr. Fox said, the use of miRNA may have less weight. "The miRNA biomarker seems very preliminary, he said, adding that in these types of investigations, the risk of false-discovery—finding an association that occurred by chance alone—is very high.

A confirmatory analysis with a second, independent dataset is needed," Dr. Fox said. "So, to me, the miRNA is interesting, but should be considered highly preliminary until a second analysis is done on a different dataset."

He added: "I don't think either of these characterizations are ready for the clinic yet. The miRNA need confirmations; the MRI phenotypes need further study to understand their clinical implications and relevance to patient management."

Drs. Hemond and Fox disclosed no relevant disclosures.

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MS Virtual 2020 Abstract PS03.01: Hemond C, Healy B, Tauhid S, et al. MRI phenotypes and miRNA signatures in MS.

Hemond CC, Healy BC, Tauhid S, et al. MRI phenotypes in MS: Longitudinal changes and miRNA signatures. Neurol Neuroimmunol Neuroinflamm 2020; Epub 2019 Feb 15.

Saturday, September 12, 2020

Disease-modifying therapies may delay disability progression in patients with primary progressive multiple sclerosis (PPMS) if they are treated early in the course of their disease, according to data presented during MS Virtual 2020, the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.

The earlier individuals were started on disease-modifying treatment, the longer it took for their disability to progress to the point where they had to use a wheelchair—reflected in a score of 7 on the Expanded Disability Status Scale (EDSS), study author Massimo Filippi, MD, professor of neurology at  Vita-Salute San Raffaele University, and chair of neurology at the MS Center and Neuroimaging Research Unit at San Raffaele Hospital in Milan, Italy, told Neurology Today At the Meetings.

Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients' long-term disability outcomes, he said. To optimize treatment decision-making in PPMS, further profiling of the best candidates for treatment is needed.

"Our findings suggest that these patients could benefit from an early treatment start that could reduce, at least partially, the accumulation of clinical disability," Dr. Filippi said. "This could have relevant implications in the management of PPMS patients."

Using the Italian MS Registry, the researchers identified 1,214 patients with PPMS who had at least three EDSS evaluations and three-years of follow-up; 790 (65 percent) of the group received a disease-modifying treatment. The first EDSS evaluation was considered the baseline for that person in the study for untreated patients, and the date of the first disease-modifying therapy as initiation for treated patients.

After a mean follow-up of 11.6 years, 994 individuals, or 82 percent of the entire sample, had an EDSS score of 6, that is, they required intermittent or unilateral constant assistance with a cane, crutch, or brace to walk about 100 meters with or without resting; 539 patients (44 percent) reached an EDSS score of 7, meaning they were unable to walk beyond approximately five meters even with aid and were essentially restricted to a wheelchair.

When the patients were stratified by those who received treatment and those who did not receive disease-modifying therapy, there was no statistically significant difference in the time to decline where wheelchair use was required.

Patients in the top quartile of use of disease-modifying agents had a 27 percent decreased risk of reaching an EDSS of 7, however, when compared with patients in the lowest quartile of use, Dr. Filippi reported.

The researchers noted that the average time from MS diagnosis to use of disease-modifying therapy was about 6.8 years. And the individuals treated the longest and in the top tier of disease-modifying drug use were generally younger, with an average age of 44.1 years at the time they first received the drugs.

"This new treatment paradigm is rewarding for several reasons," Dr. Filippi said. "Results from different randomized controlled trials and observational studies in progressive MS have consistently shown that specific disease-modifying drugs are more effective in patients who are younger and have a shorter disease duration."

"This is not surprising, because these patients typically present a higher inflammatory activity that is the main target of the different MS treatments currently available," he explained. "Conversely, in patients who are older, have a longer disease duration, and show a more severe disability, the beneficial effects of MS treatments are more limited. Accordingly, in these latter patients, the balance between treatment benefits and risk is less favorable."

Commenting on the study, Stephen Krieger, MD, FAAN, associate professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City, said: "This large real-world study is worthwhile because we really can't do these long-term studies in clinical trials."

"It is disappointing they didn't find a difference between taking medication or not, but there may be a lot of reasons for that," Dr. Krieger said. "It could be that the patients treated with disease-modifying therapy were progressing more rapidly. It is hard to control for that even in a propensity score analysis. It is hard to adjust for all things."

Dr. Krieger noted that the researchers did find that earlier treatment among those who received treatment did show a delay to the need for use of a wheelchair. "That makes sense," he said, "because it often takes longer for a drug to exert its therapeutic effect."

He said that because most of the patients were using drugs designed to help people with relapsing-remitting multiple sclerosis rather than treatment for progressive disease—and some patients had a benefit from the treatment—it supports a theory that the distinction between relapsing-remitting disease and progressive disease is somewhat blurred.

"There is a lot of overlap between what we conceive of as relapsing disease and primary progressive multiple sclerosis. These data sort that notion," Krieger said.

Dr. Filippi disclosed relationships with Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Krieger disclosed relationships with Biogen, EMD Sorono, Genentech, Genzyme, Mallinckrodt, MedDay, Novartis, Teva, and TG Therapeutics.

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MS Virtual 2020 Abstract PS05.04: Fonderico M, Portaccio E, Iaffaldano, et al. Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: A real-life cohort.

Lorscheider J, Kuhle J, Izquierdo G, et al, for the MSBase Study Group. Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: A cohort study. Eur J Neurol 2019;26(2):363-370.