Multiple Sclerosis: Focus on Extracellular and Artificial Vesicles, Nanoparticles as Potential Therapeutic Approaches

Multiple sclerosis (MS) is an autoimmune disease of the Central Nervous System, characterized by an inflammatory process leading to the destruction of myelin with neuronal death and neurodegeneration. In MS, lymphocytes cross the blood-brain barrier, creating inflammatory demyelinated plaques located primarily in the white matter. MS potential treatments involve various mechanisms of action on immune cells, immunosuppression, inhibition of the passage through the blood-brain barrier, and immunotolerance. Bio-nanotechnology represents a promising approach to improve the treatment of autoimmune diseases by its ability to affect the immune responses. The use of nanotechnology has been actively investigated for the development of new MS therapies. In this review, we summarize the results of the studies on natural and artificial vesicles and nanoparticles, and take a look to the future clinical perspectives for their application in the MS therapy.

A focus on allogeneic mesenchymal stromal cells as a versatile therapeutic tool for treating multiple sclerosis

Multiple sclerosis (MS) is a central nervous system (CNS) chronic illness with autoimmune, inflammatory, and neurodegenerative effects characterized by neurological disorder and axonal loss signs due to myelin sheath autoimmune T cell attacks. Existing drugs, including disease-modifying drugs (DMD), help decrease the intensity and frequency of MS attacks, inflammatory conditions, and CNS protection from axonal damage. As they cannot improve axonal repair and show side effects, new therapeutic options are required. In this regard, due to their neuroprotection properties, immunomodulatory effects, and the ability to differentiate into neurons, the transplantation of mesenchymal stromal cells (MSCs) can be used for MS therapy. The use of adipose-derived MSCs (AdMSCs) or autologous bone marrow MSCs (BMSCs) has demonstrated unexpected effects including the invasive and painful isolation method, inadequate amounts of bone marrow (BM) stem cells, the anti-inflammatory impact reduction of AdMSCs that are isolated from fat patients, and the cell number and differentiation potential decrease with an increase in the age of BMSCs donor. Researchers have been trying to search for alternate tissue sources for MSCs, especially fetal annexes, which could offer a novel therapeutic choice for MS therapy due to the limitation of low cell yield and invasive collection methods of autologous MSCs. The transplantation of MSCs for MS treatment is discussed in this review. Finally, it is suggested that allogeneic sources of MSCs are an appealing alternative to autologous MSCs and could hence be a potential novel solution to MS therapy.

SARS-CoV-2 Infection in Multiple Sclerosis

ObjectiveTo understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments.MethodsRetrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome.ResultsOf the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04–1.17) as the only independent risk factor for a fatal outcome.ConclusionsThis study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

The effects of PDE inhibitors on multiple sclerosis: a review of in vitro and in vivo models

Background: Multiple sclerosis (MS) is a chronic inflammatory and immune-mediated disease, whose current therapeutic means are mostly effective in the relapsing-remitting form of MS, where inflammation is still prominent, but fall short of preventing long term impairment. However, apart from inflammation-mediated demyelination, autoimmune mechanisms play a major role in MS pathophysiology, constituting a promising pharmacological target. Phosphodiesterase (PDE) inhibitors have been approved for clinical use in psoriasis and have undergone trials suggesting their neuroprotective effects, rendering them eligible as an option for accessory MS therapy. Objective: In this review, we discuss the potential role of PDE inhibitors as a complementary MS therapy. Methods: We conducted a literature search through which we screened and comparatively assessed papers on the effects of PDE inhibitor use, both in vitro and in animal models of MS, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that PDE inhibitors promote remyelination and axonal sustenance, while curbing inflammatory cell infiltration, hindering oligodendrocyte and neuronal loss and suppressing cytokine production. In vivo studies underlined that these agents alleviate symptoms and reduce disease scores in MS animal models. Conclusion: PDE inhibitors proved to be effective in addressing various aspects of MS pathogenesis both in vitro and in vivo models. Given the latest clinical trials proving that the PDE4 inhibitor Ibudilast exerts neuroprotective effects in patients with progressive MS, research on this field should be intensified and selective PDE4 inhibitors with enhanced safety features should be seriously considered as prospective complementary MS therapy.

Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.

Improvement of Comorbid Psoriasis in Patients With MS Treated With Natalizumab

ObjectiveTo present observations on administration of natalizumab to 18 patients with the comorbid MS and psoriasis, who represented a full subset of patients with such comorbidity within the patient records available.MethodsA retrospective analysis of patient records was performed. Patient histories were gathered and included date of diagnosis of MS and psoriasis, MS disease-modifying therapies (DMTs), Expanded Disability Status Scale (EDSS), reason for DMT switch, and effects on MS and psoriasis status.ResultsOn initiation of natalizumab, all 18 patients had a complete cessation of MS disease activity (within 2–8 months) with significant patient-reported improvement of psoriasis (within 1–5 months). This improvement was independent of previous MS therapy and led to 15 of 18 patients needing no additional treatment for MS and psoriasis (remaining 3 patients continued to use topical treatments for psoriasis).ConclusionsIn this cohort of 18 patients with comorbid MS and psoriasis, beneficial results on both diseases were observed after initiation of therapy with natalizumab.