The Selective Agonist for Sphingosine-1-Phosphate Receptors Siponimod Increases the Expression Level of NR4A Genes in Microglia Cell Line.

Fingolimod (FTY720) and siponimod (BAF312) are selective agonists for sphingosine-1-phosphate (S1P) receptors approved for the treatment of relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), respectively. BAF312 exerts pro-myelination and neuro-protective functions on CNS resident cells, although the underlying molecular mechanism is not yet fully understood. NR4A2 is an anti-inflammatory gene, belonging to the NR4A family, whose expression is reduced in blood from treatment-naïve patients with RRMS, but is restored in patients treated with FTY720 for more than two years. We performed an in vitro study to investigate the potential involvement of the NR4A genes in the protective and restorative effects of BAF312. We showed that BAF312 enhances the expression of NR4A1 and NR4A2 in the N9 microglial cell line, but has no effect in the peripheral blood mononuclear cells and oligodendrocytes. This study suggests a novel molecular mechanism of action for the selective agonists for S1P receptors within the CNS.

NURR1-deficient mice have age- and sex-specific behavioral phenotypes.

The transcription factor NURR1 is essential to the generation and maintenance of midbrain dopaminergic (mDA) neurons and its deregulation is involved in the development of dopamine (DA)-associated brain disorders, such as Parkinson's disease (PD). The old male NURR1 heterozygous knockout (NURR1-KO) mouse has been proposed as a model of PD due to its altered motor performance that was, however, not confirmed in a subsequent study. Based on these controversial results, we explored the effects of the NURR1 deficiency on locomotor activity, motor coordination, brain and plasma DA levels, blood pressure and heart rate of old mice, also focusing on the potential effect of sex. As a probable consequence of the role of NURR1 in DA pathway, we observed that the old NURR1-KO mouse is characterized by motor impairment, and increased brain DA level and heart rate, independently from sex. However, we also observed an alteration in spontaneous locomotor activity that only affects males. In conclusion, NURR1 deficiency triggers sex- and age-specific alterations of behavioral responses, of DA levels and cardiovascular abnormalities. Further studies in simplified systems will be necessary to dissect the mechanism underlying these observations.

Tailoring Rituximab According to CD27-Positive B-Cell versus CD19-Positive B-Cell Monitoring in Neuromyelitis Optica Spectrum Disorder and MOG-Associated Disease: Results from a Single-Center Study.

INTRODUCTION: B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates. METHODS: This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs). RESULTS: A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09-16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78-14.23) before CD27 monitoring and 15.93 months (range 8.56-35.37) after CD27 monitoring (p < 0.001). We observed no AEs. CONCLUSION: Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy.

sNFL applicability as additional monitoring tool in natalizumab extended interval dosing regimen for RRMS patients.

INTRODUCTION: Extended interval dosing (EID) of Natalizumab (NAT) has been proposed to reduce progressive multifocal leukoencephalopathy (PML) risk associated with standard interval dosing (SID) in people with multiple sclerosis (MS). Previous studies have suggested that NAT effectiveness is maintained in the great majority of patients who switch from SID to EID; monitoring of disease activity is currently based exclusively on clinical and MRI parameters. Frequent MRI are expensive and not always applicable, underlining the need for biological markers able to detect central nervous system lesions. Serum Neurofilament-light chain (sNFL) currently represents the most promising biomarker of disease activity, prognosis and treatment response in MS, and their clinical suitability is increasingly evident. The objective of the present study is to assess the applicability of sNFL as additional/alternative measure of treatment efficacy during EID regimen. METHODS: We measured sNFL by Simoa technology in longitudinal samples from 63 Relapsing Remitting (RR) MS patients switched from SID to EID. INCLUSION CRITERIA: diagnosis of RRMS, age 18-60 years; NAT SID for at least 12 months; NEDA-3 (no evidence of disease activity) for at least 12 months; availability of at least 2 serum samples collected 6 months apart. Patients' follow-up time during EID was at least 12 months and 2 blood samples were collected after at least 6 and 12 months. Clinical examination was performed before each infusion, while MRI 6 and 12 months after NAT initiation and according to PML risk during the whole study. RESULTS: No patients showed clinical or MRI activity during the whole follow-up. sNFL levels measured during SID and EID were comparable, without significant difference between groups. The effect of EID on NFL levels did not show significant effects (LMM, p> 0.05) and sNFL levels did not vary with time during SID or EID protocols (LMM, p> 0.05). Intra-individual sNFL levels demonstrated overall stability during SID and EID (median CV=11% between SID and EID samples). According to our previously published reference values, sNFL levels were in the normal range in all samples, both during SID and EID. CONCLUSIONS: Our results suggest that sNFL quantification can be used as an alternative/additional approach to MRI in managing individual patients. The present work provides a new clinical application of sNFL to monitor NAT efficacy.