Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients.

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-ß (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-ß: TNF-α and TGF-ß: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.

Exosome Content-Mediated Signaling Pathways in Multiple Sclerosis.

Exosomes are small extracellular vesicles with a complex lipid-bilayer surface and 30-150 nm diameter. These vesicles play a critical role in intercellular signaling networks during physiopathological processes through data trafficking and cell reprogramming. It has been demonstrated that exosomes are involved in a variety of central nervous system (CNS) disorders such as multiple sclerosis (MS). Exosome mediators' cell-to-cell communication is possibly by delivering their contents such as proteins, RNAs (coding and non-coding), DNAs (mitochondrial and genomic), and transposable elements to the target cells. Exosomal microRNAs (miRNAs) differ in their expression patterns in MS disease, thereby providing novel diagnostic and prognostic biomarkers and therapeutic options for better treatment of MS disease. Furthermore, these microvesicles are non-immunogenic and non-toxic therapeutic tools for transferring miRNAs across the blood-brain barrier (BBB). Collectively, exosomes could be used as novel drug delivery devices for the treatment of MS patients. This review summarized research regarding the exosomes from serum, plasma, PBMC, and other cells in MS patients and experimental models. We also provide a critical view of exosome content-mediated signaling pathways in MS, including TNF-α, TGF-ß, NF-κB, and Wnt pathways. The use of exosomes as a therapeutic potential in MS has also been discussed.

Safety and Effectiveness of Cinnomer® on Disease Characteristics, Depression, and Quality of Life of Patients with Multiple Sclerosis: A Phase IV, Post-marketing, Prospective, Multicenter Study.

BACKGROUND: Every patient diagnosed with definite multiple sclerosis (MS) should begin disease modifying therapies. Cinnomer® contains 40 mg glatiramer acetate (GA) and is available in prefilled syringes and autoinjector devices. METHODS: A phase IV multicenter study was conducted to explore the safety and effectiveness of Cinnomer® in the treatment of MS. Study-related data were collected for 14 months. RESULTS: Totally, 368 Iranian relapsing-remitting MS patients in nine cities were enrolled. The patients were either treatment naïve (n=191) or switchers (n=177). Cinnomer® treatment was associated with a significant reduction in annual relapse rate (ARR) (RR: 0.65, 95% CI: 0.43, 0.98). Final mean Expanded Disability Status Scale (EDSS) scores showed improvement from baseline (difference: -0.21, 95% confidence interval (CI): -0.34, -0.08). There was a significant decrease in gad-enhancing lesions during treatment (difference: -0.38, 95% CI: -0.64, -0.12). The mean score for the depression measure (21-item BDI-II questionnaire) significantly improved (difference: -2.39, 95% CI: -3.74, -1.03). There was a significant change in the "psychological well-being" dimension (P=0.02) (in line with BDI-II scores) and "rejection" MusiQoL dimensions (P=0.04). The adverse events documented throughout the study were not unexpected for GA and were principally not serious. CONCLUSION: Safety measures were in line with the known profiles of GA. The results suggest that Cinnomer® is effective with respect to clinical outcomes and from the patient's perspective and in reducing MRI-measured MS activity.