Cyxone Announce Dosing of First Volunteer in T20K’s First-in-human Trial
Cyxone Announce Dosing of First Volunteer in T20K’s First-in-human Trial
Sema3A and miR-497-5p can be considered critical targets for further studies on future treatments of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis
Negative Regulation of Semaphorin-3A Expression in Peripheral Blood Mononuclear Cells Using MicroRNA-497-5p.
Iran J Med Sci. 2019 Jul;44(4):325-333
Authors: Shapoori S, Ganjalikhani-Hakemi M, Rezaeepoor M, Alsahebfosoul F, Khosravi S, Etemadifar M, Mansourian M
Background: Semaphorin-3A (Sema3A), as a secreted semaphorin, is an immune modulator molecule participating in the pathogenesis of autoimmune diseases. MicroRNAs (miRNAs) modulate the target-gene expression at the post-transcriptional level. It has been proposed that miRNAs may be crucial to the modulation of the function of semaphorins. Previous findings have proven that miR-497-5p is upregulated and Sema3A is downregulated in some autoimmune disorders. Thus, we aimed to examine the presence of any correlation between Sema3A and miR-497-5p in peripheral blood mononuclear cells (PBMCs).
Methods: PBMCs were cultured and transfected with miR-497-5p mimic using the X-tremeGENE™ reagent. The expression level of Sema3A was assessed after 48 hours in supernatants and cells via the enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. Cell viability was evaluated using the methylthiazol tetrazolium assay. All the experiments were done in triplicate, and the statistical analyses were performed with SPSS, version 20. P values equal to or less than 0.05 were considered significant.
Results: We observed downregulation of the Sema3A gene (P=0.0001) and its secretion (P=0.032) in the PBMCs through miR-497-5p transfection. Moreover, transfection with miR-497-5p mimic and downregulation of Sema3A did not affect the viability of the PBMCs (P=0.061).
Conclusion: Based on the obtained results, we suggest that miR-497-5p has a high suppressive effect on Sema3A expression and both Sema3A and miR-497-5p can be considered critical targets for further studies on future therapeutic attempts for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
PMID: 31439976 [PubMed]
Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis.
Mult Scler Relat Disord. 2019 Jun 26;35:19-25
Authors: Baker D, Jacobs BM, Gnanapavan S, Schmierer K, Giovannoni G
There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.
PMID: 31279232 [PubMed – as supplied by publisher]
potential advantages and limitations of miRNAs as next generation targets in multiple sclerosis
MicroRNAs change the games in central nervous system pharmacology.
Biochem Pharmacol. 2019 Jun 25;:
Authors: Davide M, Stefano R, Marta F, Davide L
MicroRNAs (miRNAs) represent a class of important post-transcriptional regulators of gene expression, enabling cells to follow their intrinsic developmental program. By directly binding to their targets, miRNAs can both promote transcriptional patterns in crucial steps of cell growth, and act as powerful buffering system that titrate protein content in case of aberrant gene expression. The literature of the last decade showed that the presence of tissue-enriched miRNAs in body fluids could be reminiscent of disease state. This is particularly relevant in neurodegenerative disorders, in which peripheral biomarkers could be helpful means to detect disease onset. However, dysregulation of miRNAs is not merely a consequence of disease, but directly contributes to pathological outcomes. On this basis, increasing interest is growing in the development of pharmacological agents targeting specific miRNAs. Actually, this apparently futuristic approach is already part of the current therapies. In fact, several drugs approved for CNS disorders, such as L-Dopa or valproic acid, were also demonstrated to restore some miRNAs. Moreover, ongoing clinical trials demonstrated that miRNA-based drugs are effective against tumors, suggesting that miRNAs also represent a promising class of therapeutic molecules. However, several issues still need to be addressed, particularly in case of CNS diseases, in which stability and delivery are crucial aspects of the therapy. In this commentary, we highlighted potential advantages and limitations of miRNAs as next generation targets in CNS pharmacology, focusing on multiple sclerosis, a chronic demyelinating disease lacking specific therapeutic targets and bona-fide biomarkers.
PMID: 31251938 [PubMed – as supplied by publisher]
Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.
N Engl J Med. 2019 06 20;380(25):2406-2417
Authors: Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS, Evobrutinib Phase 2 Study Group
BACKGROUND: Bruton’s tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.
METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).
RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.
CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).
PMID: 31075187 [PubMed – indexed for MEDLINE]
A review for the neuroprotective effects of andrographolide in the central nervous system.
Biomed Pharmacother. 2019 Jun 07;117:109078
Authors: Lu J, Ma Y, Wu J, Huang H, Wang X, Chen Z, Chen J, He H, Huang C
Andrographolide is compound extracted from Andrographis paniculata (A. paniculata), a traditional herb that has been used in ancient China and other parts of eastern Asia to treat an array of disorders, such as cancer, rheumatoid arthritis, diarrhea, upper respiratory tract infection, and laryngitis, for a very long history. The mechanisms of action of andrographolide in disease prevention and/or therapy include anti-inflammation, anti-oxidative stress, anti-apoptosis, and/or pro-apoptosis. Pharmacodynamic studies have shown that andrographolide can cross the blood brain barrier and distribute into different brain regions, and therefore its pharmacological effects in the central nervous system (CNS) have begun to be revealed in recent years. For example, andrographolide has been reported to reduce brain infarct volume in several models of cerebral ischemia. In models of Alzheimer’s disease (AD), andrographolide not only reduces Aβ aggregation, but suppresses neuroinflammatory response and synaptic dysfunction, which could be evidenced by the reversal of microglia-mediated production of pro-inflammatory cytokines as well as AD-associated decreases in synaptic proteins, such as postsynaptic membrane dense substance-95. Andrographolide may also inhibit the onset and/or progression of Parkinson’s disease, multiple sclerosis, and surgery- or diabetes-induced cognitive impairment. Further, andrographolide has been shown to inhibit chronic stress-induced abnormalities in serum corticosterone levels, mood-associated behavior, and hippocampal neurogenesis, suggesting that andrographolide may have a potential to treat psychiatric disorders, such as anxiety and depression. In this review, we summarize and discuss the pharmacological effects of andrographolide in the CNS in hope of revealing more possibilities of andrographolide in disease prevention and/or therapy.
PMID: 31181444 [PubMed – as supplied by publisher]
The gut microbiota perspective for interventions in MS.
Autoimmun Rev. 2019 Jun 06;:
Authors: Zoledziewska M
The heritable genetic variation that explains phenotypic differences in a population fluctuates for different autoimmune disorders. Particularly in multiple sclerosis (MS) etiology, modest genetic and major environmental effects emerge. Increasingly recognized as a major environmentally shaped contributor to disease and treatment outcomes are gut microbiota. As discussed here, the observed impact of gut microbiome on MS pathophysiology, involves both quantitative and functional changes in composition, metabolism, gut permeability, homeostasis and modulation of the immune system. Although the first supplementary therapeutic interventions have been approached in general autoimmune disorders they are relatively cruder and a translation of knowledge from other pathologies is valuable but still required. Consequently initial therapeutic interventions with microbiota for autoimmune disorders could be correspondingly improved.
PMID: 31176875 [PubMed – as supplied by publisher]
P2X7 receptor: A potential therapeutic target for autoimmune diseases.
Autoimmun Rev. 2019 Aug;18(8):767-777
Authors: Cao F, Hu LQ, Yao SR, Hu Y, Wang DG, Fan YG, Pan GX, Tao SS, Zhang Q, Pan HF, Wu GC
P2X7 receptor (P2X7R), a distinct ligand-gated ion channel, is a member of purinergic type 2 receptor family with ubiquitous expression in human body. Previous studies have revealed a pivotal role of P2X7R in innate and adaptive immunity. Once activated, it will meditate some vital cascaded responses including the assembly of nucleotide-binding domain (NOD) like receptor protein 3 (NLRP3) inflammasome, non-classical secretion of IL-1β, modulation of cytokine-independent pathways in inflammation such as P2X7R- transglutaminase-2 (TG2) and P2X7R-cathepsin pathway, activation and regulation of T cells, etc. In fact, above responses have been identified to be involved in the development of autoimmunity, specifically, the NLRP3 inflammasome could promote inflammation in massive autoimmune diseases and TG2, as well as cathepsin may contribute to joint destruction and degeneration in inflammatory arthritis. Recently, numerous evidences further suggested the significance of P2X7R in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), etc. In this review, we will succinctly discuss the biological characteristics and summarize the recent progress of the involvement of P2X7R in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
PMID: 31181327 [PubMed – indexed for MEDLINE]
Nanotechnology treatment shows promise against multiple sclerosis
A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis.
Mult Scler. 2019 May 30;:1352458519849513
Authors: Pellegrini F, Copetti M, Bovis F, Cheng D, Hyde R, de Moor C, Kieseier BC, Sormani MP
BACKGROUND: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores.
OBJECTIVE: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.
RESULTS: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13-0.55) versus 0.62 (95% CI = 0.47-0.83) for all other responders (heterogeneity p = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18-0.56) and 0.61 (95% CI = 0.47-0.79; heterogeneity p = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale.
CONCLUSION: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.
PMID: 31144577 [PubMed – as supplied by publisher]
Plasma protein profiling reveals candidate biomarkers for multiple sclerosis treatment.
PLoS One. 2019;14(5):e0217208
Authors: Bedri SK, Nilsson OB, Fink K, Månberg A, Hamsten C, Ayoglu B, Manouchehrinia A, Nilsson P, Olsson T, Hillert J, Grönlund H, Glaser A
Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.
PMID: 31141529 [PubMed – in process]
Conditions : Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
Intervention : Drug: Cladribine
Sponsor : Washington University School of Medicine
Not yet recruiting
Cladribine Tablets: Collaborative Study to Evaluate Impact On Central Nervous System Biomarkers in Multiple Sclerosis
Fri, 24 May 2019 12:00:00 EDT
First Added: 05/24/19 06:51AM
Condition : Multiple Sclerosis
Intervention : Drug: Cladribine
Sponsors : EMD Serono Research & Development Institute, Inc.; Merck KGaA, Darmstadt, Germany
Not yet recruiting
Long-Term Outcomes and Durability of Effect Following Treatment With Cladribine Tablets for Multiple Sclerosis (MS)
Thu, 23 May 2019 12:00:00 EDT
First Added: 05/23/19 07:47AM
Pharmacoeconomics of synthetic therapies for multiple sclerosis.
Expert Opin Pharmacother. 2019 Aug;20(11):1331-1340
Authors: D’Amico E, Chisari CG, Gitto L, Zanghì A, Toscano S, Patti F
Introduction: Recently, the economic impact of multiple sclerosis (MS), which includes both direct and indirect costs, has been increasing. While direct costs comprise health-care costs, such as the cost of pharmaceuticals, additional treatments such as physiotherapy, and medical aids, indirect costs are triggered by the productivity loss of patients and caregivers. Although new drugs for MS have changed the therapeutic scenario, they have increased the direct costs of health-care services. Areas covered: This review describes the pharmacoeconomic aspects of synthetic therapies for MS. Additionally, it discusses the economic impact of the various classes of licensed disease-modifying treatments (DMTs) for relapsing forms of MS. Expert opinion: The emerging and more expensive DMTs for MS represent a considerable challenge for health-care systems and resource consumption. Future research should focus on the long-term efficacy of DMTs and the cost of treating MS in a real-life setting. Future biological and radiological biomarkers could help stratify patients at early stages of MS, helping physicians design a personalized therapeutic approach that could have a positive impact in economic terms.
PMID: 31090469 [PubMed – indexed for MEDLINE]
Condition : Multiple Sclerosis
Intervention : Other: Spa therapy
Sponsor : Association Francaise pour la Recherche Thermale
Not yet recruiting
Thermal Cures in the Treatment of Multiple Sclerosis
Mon, 15 Apr 2019 12:00:00 EDT
First Added: 04/16/19 08:22AM
Therapeutic effect of transplanted umbilical cord mesenchymal stem cells in a cynomolgus monkey model of multiple sclerosis.
Am J Transl Res. 2019;11(4):2516-2531
Authors: Liu S, Wang J, Han R, Meng M, Wang W, Zhao Y, Yang F, Yang L, Gao H, Zhao Y, Yang L, Wang R, Tang W, Li Y, Duan S, Wang J, He Z, Li L, Hou Z
Multiple sclerosis (MS) is a demyelinating disease affecting 2.5 million young people worldwide because of its immune-mediated pathological mechanisms. Recent studies have shown that stem cell transplantation is a new potential therapy for MS. There has been renewed interest in cell therapy to improve quality of life for MS patients. In this study, the experimental autoimmune encephalomyelitis (EAE) model, which is the most commonly model to mimic MS, was successfully established in cynomolgus monkeys. To evaluate the therapeutic effect of human umbilical cord mesenchymal stem cells (UCMSCs) on MS, we intravenously transplanted UCMSCs into cynomolgus monkeys with EAE. Our results showed that UCMSC transplantation significantly ameliorated the clinical symptoms of MS. Magnetic resonance imaging and clinical signs indicated that demyelination was obviously decreased after UCMSCs therapy. Moreover, the present study showed that the mechanisms, involved in the effects of UCMSCs on MS, included their immunomodulatory functions to regulate cytokine secretion and affect functional differentiation of the T cell lineage.
PMID: 31105859 [PubMed]
Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.
Cell Metab. 2018 Jun 05;27(6):1222-1235.e6
Authors: Cignarella F, Cantoni C, Ghezzi L, Salter A, Dorsett Y, Chen L, Phillips D, Weinstock GM, Fontana L, Cross AH, Zhou Y, Piccio L
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
PMID: 29874567 [PubMed – indexed for MEDLINE]
Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives.
Biomedicines. 2019 Mar 30;7(2):
Authors: Cuascut FX, Hutton GJ
Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.
PMID: 30935074 [PubMed]
Sulforaphane-enriched broccoli sprouts might be a potential nutraceutical with antineuroinflammatory and neuroprotective effects
Sulforaphane-Enriched Broccoli Sprouts Pretreated by Pulsed Electric Fields Reduces Neuroinflammation and Ameliorates Scopolamine-Induced Amnesia in Mouse Brain through Its Antioxidant Ability via Nrf2-HO-1 Activation.
Oxid Med Cell Longev. 2019;2019:3549274
Authors: Subedi L, Cho K, Park YU, Choi HJ, Kim SY
Activated microglia-mediated neuroinflammation plays a key pathogenic role in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ischemia. Sulforaphane is an active compound produced after conversion of glucoraphanin by the myrosinase enzyme in broccoli (Brassica oleracea var) sprouts. Dietary broccoli extract as well as sulforaphane has previously known to mitigate inflammatory conditions in aged models involving microglial activation. Here, we produced sulforaphane-enriched broccoli sprouts through the pretreatment of pulsed electric fields in order to trigger the biological role of normal broccoli against lipopolysaccharide-activated microglia. The sulforaphane-enriched broccoli sprouts showed excellent potency against neuroinflammation conditions, as evidenced by its protective effects in both 6 and 24 h of microglial activation in vitro. We further postulated the underlying mechanism of action of sulforaphane in broccoli sprouts, which was the inhibition of an inflammatory cascade via the downregulation of mitogen-activated protein kinase (MAPK) signaling. Simultaneously, sulforaphane-enriched broccoli sprouts inhibited the LPS-induced activation of the NF-κB signaling pathway and the secretions of inflammatory proteins (iNOS, COX-2, TNF-α, IL-6, IL-1β, PGE2, etc.), which are responsible for the inflammatory cascades in both acute and chronic inflammation. It also upregulated the expression of Nrf2 and HO-1 in normal and activated microglia followed by the lowered neuronal apoptosis induced by activated microglia. Based on these results, it may exhibit anti-inflammatory effects via the NF-κB and Nrf2 pathways. Interestingly, sulforaphane-enriched broccoli sprouts improved the scopolamine-induced memory impairment in mice through Nrf2 activation, inhibiting neuronal apoptosis particularly through inhibition of caspase-3 activation which could lead to the neuroprotection against neurodegenerative disorders. The present study suggests that sulforaphane-enriched broccoli sprouts might be a potential nutraceutical with antineuroinflammatory and neuroprotective activities.
PMID: 31049133 [PubMed – indexed for MEDLINE]
Mesenchymal Stem Cell Therapies in Brain Disease.
Semin Cell Dev Biol. 2019 Mar 25;:
Authors: Sherman LS, Romagano MP, Williams SF, Rameshwar P
As treatments for diseases throughout the body progress, treatment for many brain diseases has been at a standstill due to difficulties in drug delivery. While new drugs are being discovered in vitro, these therapies are often hindered by inefficient tissue distribution and, more commonly, an inability to cross the blood brain barrier. Mesenchymal stem cells are thus being investigated as a delivery tool to directly target therapies to the brain to treat wide array of brain diseases. This review discusses the use of mesenchymal stem cells in hypoxic disease (Hypoxic Ischemic Encephalopathy), an inflammatory neurodegenerative disease (Multiple Sclerosis), and a malignant condition (glioma).
PMID: 30922957 [PubMed – as supplied by publisher]
Condition : Multiple Sclerosis
Intervention : Device: transcranial direct current stimulation
Sponsors : University of Iowa; jkamholz; cdworkman
Not yet recruiting
tDCS to Lower Neuropathic Pain and Fatigue in People With Multiple Sclerosis
Mon, 11 Mar 2019 12:00:00 EDT
Last Update Posted: 03/11/19 10:02AM
Condition : Multiple Sclerosis, Relapsing-remitting
Intervention : Dietary Supplement: Vitamin D3
Sponsors : Johns Hopkins University; University of California, San Francisco; National Multiple Sclerosis Society
Pharmacokinetics of Vitamin D in Multiple Sclerosis and in Health
Fri, 17 Aug 2012 12:00:00 EDT
Last Update Posted: 03/05/19 08:58AM
Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis.
J Cell Physiol. 2019 Feb 27;:
Authors: Gharesouran J, Taheri M, Sayad A, Mazdeh M, Omrani MD
Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.
PMID: 30815864 [PubMed – as supplied by publisher]
Therapeutic effect of oligomeric proanthocyanidin in cuprizone-induced demyelination.
Exp Physiol. 2019 Feb 27;:
Authors: Wang Q, Wang J, Yang Z, Sui R, Miao Q, Li Y, Yu J, Liu C, Zhang G, Xiao B, Ma C
NEW FINDINGS: What is the central question of this study? Oligomeric proanthocyanidin (OPC) has the capacity to alleviate abnormalities in neurological functioning. However, whether OPC can reduce the progression of demyelination or promote remyelination in demyelinating diseases remains unknown. What is the main finding and its importance? OPC can improved cuprizone (CPZ)-induced demyelination by inhibiting immune cell infiltration, reversing over-activated microglia, decreasing the inflammatory cytokines secreted by inflammatory cells and decreasing the production of MOG35-55 specific antibody in the brain.
ABSTRACT: Demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS), neuromyelitis optica, acute disseminated encephalomylitis, are characterized by recurrent primary demyelination/remyelination and progressive neurodegeneration. In the present study, we investigate the therapeutic effect of oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract, in cuprizone (CPZ)-fed C57BL/6 mice, a classic demyelination/remyelination model. Our results show that OPC attenuated abnormal behavior, reduced demyelination, and increased expression of myelin basic protein (MBP) and expression of O4+ oligodendrocytes in the corpus callosum. OPC also reduced the numbers of B cells and T cells, activated microglia in the corpus callosum, and inhibited secretion of inflammatory factors. Further, concentrations of myelin oligodendrocyte glycoprotein-specific antibodies were significantly reduced in serum and brain homogenates after OPC treatment. Together, these results demonstrate a potent therapeutic effect for OPC in CPZ-mediated demyelination and clearly highlight multiple effects of this natural product in attenuating myelin-specific autoantibodies and the inflammatory microenvironment in the brain. This article is protected by copyright. All rights reserved.
PMID: 30811744 [PubMed – as supplied by publisher]
Reduced disease severity following therapeutic treatment with angiotensin 1-7 in a mouse model of multiple sclerosis.
Neurobiol Dis. 2019 Feb 25;:
Authors: Lund BT, Stone R, Levy AM, Lee S, Amundson E, Kashani N, Rodgers KE, Kelland EE
Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease. Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1-7 (A(1-7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1-7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1-7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1-7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.
PMID: 30818065 [PubMed – as supplied by publisher]
Potential Therapeutic Features of Human Amniotic Mesenchymal Stem Cells in Multiple Sclerosis: Immunomodulation, Inflammation Suppression, Angiogenesis Promotion, Oxidative Stress Inhibition, Neurogenesis Induction, MMPs Regulation, and Remyelination Stimulation.
Front Immunol. 2019;10:238
Authors: Abbasi-Kangevari M, Ghamari SH, Safaeinejad F, Bahrami S, Niknejad H
Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system with unknown etiology. It is accompanied by demyelination of the nerves during immunological processes in the presence of oxidative stress, hypoxia, cerebral hypo-perfusion, and dysregulation in matrix metalloproteinases (MMPs). Human amniotic mesenchymal stem cells (hAMSCs) as pluripotent stem cells possess some conspicuous features which could be of therapeutic value in MS therapy. hAMSCs could mimic the cascade of signals and secrete factors needed for promoting formation of stable neovasculature and angiogenesis. hAMSCs also have immunomodulatory and immunosuppressive effects on inflammatory processes and reduce the activity of inflammatory cells, migration of microglia and inhibit recruitment of certain immune cells to injury sites. hAMSCs attenuate the oxidative stress supported by the increased level of antioxidant enzymes and the decreased level of lipid peroxidation products. Furthermore, hAMSCs enhance neuroprotection and neurogenesis in brain injuries by inhibition of inflammation and promotion of neurogenesis. hAMSCs could significantly increase the expression of neurotrophic factors, which prevents neurons from initiating programmed cell death and improves survival, development, and function of neurons. In addition, they induce differentiation of neural progenitor cells to neurons. hAMSCs could also inhibit MMPs dysregulation and consequently promote the survival of endothelial cells, angiogenesis and the stabilization of vascular networks. Considering the mentioned evidences, we hypothesized here that hAMSCs and their conditioned medium could be of therapeutic value in MS therapy due to their unique properties, including immunomodulation and inflammation suppression; angiogenesis promotion; oxidative stress inhibition; neurogenesis induction and neuroprotection; matrix metalloproteinases regulation; and remyelination stimulation.
PMID: 30842772 [PubMed – in process]
The last consider the hypothesis of molecular mimicry mechanism, which is potentially triggered by viral antigen inducing MS autoimmunity. The Human Endogenous Retroviruses W family (HERV-W) is the subject of studies within this field, based on the detection of HERV-W envelope gene proteins in MS patients’ samples.
Cross-reactivity between myelin oligodendrocyte glycoprotein and human endogenous retrovirus W protein: nanotechnological evidence for the potential trigger of multiple sclerosis.
Micron. 2019 Feb 18;120:66-73
Authors: de Luca V, Martins Higa A, Malta Romano C, Pimenta Mambrini G, Peroni LA, Trivinho-Strixino F, Lima Leite F
Multiple sclerosis (MS) is an autoimmune and inflammatory demyelinating disease of the central nervous system. Experimental evidence supports the reactivity of autoantibodies against components of myelin sheath including the myelin oligodendrocyte glycoprotein (MOG). The MS etiology is still unknown, but some risk factors associated with immune dysregulation, genetic susceptibility, and environmental factors are under investigation. The last consider the hypothesis of molecular mimicry mechanism, which is potentially triggered by viral antigen inducing MS autoimmunity. The Human Endogenous Retroviruses W family (HERV-W) is the subject of studies within this field, based on the detection of HERV-W envelope gene proteins in MS patients’ samples. In the biomedical field of diagnosis and therapeutics, nanotechnology is of great use for the detailed study of molecular mechanisms involving specific interactions between biomolecules providing high specificity and sensitivity of response. In view of the significance of etiological aspects for the comprehension of MS mechanisms of action, we applied a nanotechnological approach designed for antibody detection. For this, we analyzed MOG peptide sequences similar to the HERV-W protein. These sequences were subjected to interaction with anti-HERV-W antibodies using atomic force spectroscopy (AFS) and silver nanoparticles (AgNPs) methods to survey the potential occurrence of molecular mimicry. Our results revealed the molecular recognition between the anti-HERV-W antibody and the HERV-W and MOG epitopes by AFS and AgNPs approaches. Specific non-linear shape of force curves and median adhesion force values within the expected range for an antigen-antibody interaction were obtained for HERV-W and MOG peptides, 163 pN and 178 pN, respectively, suggesting the occurrence of cross-reactivity in these systems.
PMID: 30802755 [PubMed – as supplied by publisher]
The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation.
Life Sci. 2019 Feb 15;219:40-73
Authors: Askari VR, Shafiee-Nick R
AIMS: Neuroinflammation is observed as a routine characterization of neurodegenerative disorders such as dementia, multiple sclerosis (MS) and Alzheimer’s diseases (AD). Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor.
METHODS: In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase).
KEY FINDINGS: The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2 receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway.
SIGNIFICANCE: In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.
PMID: 30620895 [PubMed – indexed for MEDLINE]
Frontal brain activity and cognitive processing speed in multiple sclerosis: An exploration of EEG neurofeedback training.
Neuroimage Clin. 2019 Feb 11;22:101716
Authors: Keune PM, Hansen S, Sauder T, Jaruszowic S, Kehm C, Keune J, Weber E, Schönenberg M, Oschmann P
BACKGROUND: Cognitive deficits including impaired information processing speed as assessed by the Symbol Digit Modalities Test (SDMT) are common in multiple sclerosis (MS). Oscillatory markers of processing speed may be extracted from magnetoencephalographic (MEG) and electroencephalographic (EEG) resting-state recordings. In this context, an increased proportion of frontal slow-wave (theta, 4-8 Hz) to fast-wave (beta, 13-30 Hz) EEG activity was indicative of impaired SDMT performance. Such an increased theta/beta ratio may reflect oscillatory slowing associated with deficits in attention control. Therapeutic approaches that consider atypical oscillatory activity in MS remain sparse.
OBJECTIVES: In a cross-sectional design, we examined the relation between SDMT performance, the EEG theta/beta ratio and its components. We also explored longitudinally, whether EEG neurofeedback could be used to induce a putatively adaptive alteration in these EEG parameters, toward a pattern indicative of improved processing speed.
METHODS: N = 58 MS patients (RRMS/SPMS/PPMS N: 18/35/3, 2 cases excluded) participated in a neuropsychological examination and a resting-state EEG recording. Subsequently, N = 10 patients received neurofeedback training for two weeks in a hospitalized setting. The purpose was to reduce the frontal theta/beta ratio through operant conditioning.
RESULTS: In the cross-sectional examination, patients with slow SDMT speed displayed an increased theta/beta ratio, relative to those with normal speed. This involved increased frontal theta power, whereas beta power was equal across groups. The theta/beta ratio remained stable during neurofeedback across sessions of the two-week training period. In an exploratory secondary analysis, within sessions a reduction in the theta/beta ratio during active training blocks relative pre/post session resting-states was observed, driven by reduced theta power.
CONCLUSIONS: These findings provide support for utilizing frontal EEG theta activity as an inverse marker of processing speed in MS. Across sessions, there was no support for successful operant conditioning of the theta/beta ratio during the two-week training period. The observed state-specific shift within sessions, involving a transient reduction in theta activity, nevertheless may provide a rationale for a further investigation of neurofeedback as a treatment approach in MS.
PMID: 30798167 [PubMed – as supplied by publisher]
In an outlook, we will discuss accordingly, how this potentially important aspect can be harnessed to advance future B cell-directed therapeutic approaches in multiple sclerosis and related diseases.
The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders.
Front Immunol. 2019;10:201
Authors: Häusser-Kinzel S, Weber MS
Our pathophysiological concept of the most common central nervous system demyelinating disease, multiple sclerosis, strikingly evolved by recent discoveries suggesting that B lymphocytes substantially contribute in its initiation and chronic propagation. In this regard, activated B cells are nowadays considered to act as important antigen-presenting cells for the activation of T cells and as essential source of pro-inflammatory cytokines. Hereby, they create a milieu in which other immune cells differentiate and join an orchestrated inflammatory infiltration of the CNS. Without a doubt, this scientific leap was critically pioneered by the empirical use of anti-CD20 antibodies in recent clinical MS trials, which revealed that the therapeutic removal of immature and mature B cells basically halted development of new inflammatory flares in otherwise relapsing MS patients. This stabilization occurred largely independent of any indirect effect on plasma cell-produced antibody levels. On the contrary, peripherally produced autoantibodies are probably the most important B cell component in two other CNS demyelinating diseases which are currently in the process of being delineated as separate disease entities. The first one is neuromyelitis optica in which an antibody response against aquaporin-4 targets and destroys astrocytes, the second, likely distinct entity embraces a group of patients containing antibodies against myelin oligodendrocyte glycoprotein. In this review, we will describe and summarize pro-inflammatory B cell properties in these three CNS demyelinating disorders; we will however also provide an overview on the emerging concept that B cells or B cell subsets may exert immunologically counterbalancing properties, which may be therapeutically desirable to maintain and foster in inflammatory CNS demyelination. In an outlook, we will discuss accordingly, how this potentially important aspect can be harnessed to advance future B cell-directed therapeutic approaches in multiple sclerosis and related diseases.
PMID: 30800132 [PubMed – in process]
Embargoed until February 1, 2021
B-Cell Therapies in Multiple Sclerosis.
Cold Spring Harb Perspect Med. 2019 02 01;9(2):
Authors: Sabatino JJ, Zamvil SS, Hauser SL
B cells play a vital function in multiple sclerosis (MS) pathogenesis through an array of effector functions. All currently approved MS disease-modifying therapies alter the frequency, phenotype, or homing of B cells in one way or another. The importance of this mechanism of action has been reinforced with the successful development and clinical testing of B-cell-depleting monoclonal antibodies that target the CD20 surface antigen. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved by the Food and Drug Administration (FDA) in March 2017 after pivotal trials showed dramatic reductions in inflammatory disease activity in relapsing MS as well as lessening of disability progression in primary progressive MS. These and other clinical studies place B cells at the center of the inflammatory cascade in MS and provide a launching point for development of therapies that target selective pathogenic B-cell populations.
PMID: 29358322 [PubMed – indexed for MEDLINE]
KIAA1199 expression by activated astrocytes may explain the focal HA degradation observed during progression of MS and could represent a possible new therapeutic target.
KIAA1199 expression and hyaluronan degradation colocalize in multiple sclerosis lesions
The role of B cells in multiple sclerosis: Current and future therapies.
Cell Immunol. 2019 May;339:10-23
Authors: Negron A, Robinson RR, Stüve O, Forsthuber TG
While it was long held that T cells were the primary mediators of multiple sclerosis (MS) pathogenesis, the beneficial effects observed in response to treatment with Rituximab (RTX), a monoclonal antibody (mAb) targeting CD20, shed light on a key contributor to MS that had been previously underappreciated: B cells. This has been reaffirmed by results from clinical trials testing the efficacy of subsequently developed B cell-depleting mAbs targeting CD20 as well as studies revisiting the effects of previous disease-modifying therapies (DMTs) on B cell subsets thought to modulate disease severity. In this review, we summarize current knowledge regarding the complex roles of B cells in MS pathogenesis and current and potential future B cell-directed therapies.
PMID: 31130183 [PubMed – in process]
Economic Evaluation of Stem Cell Therapies in Neurological Diseases: A Systematic Review.
Value Health. 2019 02;22(2):254-262
Authors: Nagpal A, Milte R, Kim SW, Hillier S, Hamilton-Bruce MA, Ratcliffe J, Koblar SA
OBJECTIVES: To examine economic evaluation studies of stem cell therapies (SCTs) in neurological disorders and to provide an overview of the quality of the economic evidence available on this topic.
METHODS: The review examined studies that performed an economic evaluation of the use of stem cells in adult patients with neurological diseases and that were published in English during the period 2007 to 2017. Data analyzed and reported included study population, disease indication, main analytical approaches for the economic analysis and perspective, key assumptions made or tested in sensitivity analyses, cost outcomes, estimates of incremental cost effectiveness, and approaches to quantifying decision uncertainty.
RESULTS: A total of three studies reporting on the findings of the economic evaluation of the use of SCT in stroke, Parkinson disease, and secondary progressive multiple sclerosis, respectively, were identified. All three studies conducted a cost-utility analysis using decision-analytic models and reported an incremental cost per quality-adjusted life-years gained (incremental cost-effectiveness ratio) versus standard care. These studies reported meaningful cost savings in stroke, Parkinson disease, and secondary progressive multiple sclerosis in the base-case scenarios.
CONCLUSIONS: Despite significant progress in clinical research in the use of SCT in neurological diseases, economic evaluation of these therapies is still at a nascent stage. Given the early stage of research inputs (clinical and cost outcomes data) into the models per se, further research is urgently needed to enable meaningful assessment of the cost effectiveness of these advanced therapies and to ensure sustainable access for population groups most likely to benefit in clinical practice.
PMID: 30711072 [PubMed – indexed for MEDLINE]
Systemic inhibition of the membrane attack complex impedes neuroinflammation in chronic relapsing experimental autoimmune encephalomyelitis.
Acta Neuropathol Commun. 2018 05 03;6(1):36
Authors: Michailidou I, Jongejan A, Vreijling JP, Georgakopoulou T, de Wissel MB, Wolterman RA, Ruizendaal P, Klar-Mohamad N, Grootemaat AE, Picavet DI, Kumar V, van Kooten C, Woodruff TM, Morgan BP, van der Wel NN, Ramaglia V, Fluiter K, Baas F
The complement system is a key driver of neuroinflammation. Activation of complement by all pathways, results in the formation of the anaphylatoxin C5a and the membrane attack complex (MAC). Both initiate pro-inflammatory responses which can contribute to neurological disease. In this study, we delineate the specific roles of C5a receptor signaling and MAC formation during the progression of experimental autoimmune encephalomyelitis (EAE)-mediated neuroinflammation. MAC inhibition was achieved by subcutaneous administration of an antisense oligonucleotide specifically targeting murine C6 mRNA (5 mg/kg). The C5a receptor 1 (C5aR1) was inhibited with the C5a receptor antagonist PMX205 (1.5 mg/kg). Both treatments were administered systemically and started after disease onset, at the symptomatic phase when lymphocytes are activated. We found that antisense-mediated knockdown of C6 expression outside the central nervous system prevented relapse of disease by impeding the activation of parenchymal neuroinflammatory responses, including the Nod-like receptor protein 3 (NLRP3) inflammasome. Furthermore, C6 antisense-mediated MAC inhibition protected from relapse-induced axonal and synaptic damage. In contrast, inhibition of C5aR1-mediated inflammation diminished expression of major pro-inflammatory mediators, but unlike C6 inhibition, it did not stop progression of neurological disability completely. Our study suggests that MAC is a key driver of neuroinflammation in this model, thereby MAC inhibition might be a relevant treatment for chronic neuroinflammatory diseases.
PMID: 29724241 [PubMed – indexed for MEDLINE]
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