Therapeutic Options For Multiple Sclerosis Research Articles

Adipose-derived mesenchymal stem cells ameliorates experimental autoimmune encephalomyelitis via modulation of Th1/Th17 and expansion of Th2/Treg responses.

The most common central nervous system (CNS) inflammatory disease is multiple sclerosis (MS), modeled using experimental autoimmune encephalomyelitis (EAE). Mesenchymal stem cells (MSCs) exhibit potent immunomodulatory capabilities, including the suppression of immune cell functions and anti-inflammatory cytokine production. Female C57BL/6 mice (8-10 weeks old) were divided into three groups: 1. Control, 2. Allogeneic MSCs (ALO) treatment, and 3. Syngeneic MSCs (SYN) treatment. To induce EAE, myelin oligodendrocyte glycoprotein was injected subcutaneously with complete Freund's adjuvant, followed by intraperitoneal pertussis toxin. On Days 6 and 12 postimmunization, the treatment groups received intraperitoneal injections of 2 × 106 MSCs. Daily clinical and weight assessments were performed, and on Day 25, the mice were euthanized. At the end of the period, brain histological analysis was conducted to quantify lymphocyte infiltration. T-cell characteristics were determined usingenzyme-linked immunosorbent assay and Real-time polymerase chain reaction (RT-PCR). The assessment of transcription factor expression levels in the CNS was also performed using RT-PCR. Compared to the control group, both the allogeneic (ALO) and syngeneic (SYN) groups demonstrated significantly reduced disease progression. The maximum clinical scores for the control, ALO, and SYN groups were 4.4 ± 0.1, 2.4 ± 0.2, and 2.1 ± 0.2, respectively (ALO and SYN vs. Control: p < .001). In comparison to the control group, histological studies demonstrated that the allogeneic and syngeneic groups had less lymphocytic infiltration (ALO: 1.4 ± 0.1, SYN: 1.2 ± 0.2, and control: 2.8 ± 0.15; p < .001) and demyelination (ALO: 1.2 ± 0.15, SYN: 1.1 ± 0.1 and control: 2.9 ± 0.1, p < .001). ALO and SYN groups had lower expression of Th1 and Th17 cytokines and transcription factors (IFN-γ: 0.067, 0.051; STAT4: 0.189, 0.162; T-bet: 0.175, 0.163; IL-17: 0.074, 0.061; STAT3: 0.271, 0.253; ROR-γt: 0.163, 0.149, respectively) compared to the control group on Day 25 following EAE induction. Additionally, ALO and SYN groups compared to the control group, expressed more Th2 and Treg cytokines and transcription factors (IL-4: 4.25, 4.63; STAT6: 2.78, 2.96; GATA3: 2.91, 3.08; IL-27: 2.32, 2.46, IL-33: 2.71, 2.85; TGF-β: 4.8, 5.05; IL-10: 4.71, 4.93; CTLA-4: 7.72, 7.95; PD1: 4.12,4.35; Foxp3: 3.82,4.08, respectively). This research demonstrated that MSCs possess the potential to be a therapeutic option for MS and related CNS inflammatory disorders. Their immunomodulatory properties, coupled with the observed reductions in disease severity, lymphocytic infiltration, and demyelination, indicate that MSCs could play a crucial role in altering the course of MS by mitigating inflammatory immune responses and promoting regulatory immune processes. These findings open up new possibilities for the development of MSC-based therapies for MS, and further investigation and clinical trials may be warranted to explore their efficacy and safety in human patients.

Mapping the Therapeutic Options for Multiple Sclerosis in Brazil: A Comprehensive Analysis

Multiple sclerosis is an autoimmune disease that affects the central nervous system. In Brazil, there are currently several therapeutic options for the treatment of this condition, with some being distributed free of charge, while others are not included in the list of free medications. The objective of this article is to provide a pharmacoepidemiological analysis of the available medications in the country, covering their mechanisms of action, the historical context of approval and free distribution within the healthcare system, and their geographical distribution of application. Additionally, we discuss the impact of the inclusion of these medications on hospitalization and mortality rates in the country. We hope that this work serves as a resource for healthcare professionals to better understand pharmacoepidemiology and for health policymakers seeking data for the planning of public policies aimed at the treatment of multiple sclerosis.

Stem Cell Transplantation for Multiple Sclerosis: A 2023 Review of Published Studies.

This comprehensive literature review underscores the potential of stem cell transplantation (SCT) as a therapeutic intervention for multiple sclerosis (MS). By amalgamating evidence from various sources, including randomized controlled trials (RCTs), observational, retrospective, and comparative studies, this review offers a holistic understanding of SCT's effectiveness, safety, and feasibility in diverse contexts of MS management. SCT has shown promise in mitigating disease activity and progression, particularly in relapsing-remitting MS (RRMS). RCTs like the high dose immunoablation and autologous hematopoietic stem cell transplantation in MS (ASTIMS) versus mitoxantrone therapy in severe multiple sclerosis and multiple sclerosis international stem cell transplant (MIST) trials reveal SCT's capacity to reduce new lesion occurrences and inflammatory activity. However, variability exists in disability score improvements among these studies. Observational and retrospective investigations further affirm SCT's potential, highlighting decreased relapse rates, enhanced expanded disability status scale (EDSS) scores, and a noteworthy proportion of patients achieving no evidence of disease activity (NEDA). The initial literature search using all of the search items produced a total of 3,636 articles. After title, abstract, and article type screening and article retrieving, 147 articles were assessed for eligibility using the inclusion criteria. At the end of the literature search, 37 articles met the eligibility criteria. They were included in our review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Patients treated with hematopoietic stem cell transplantation (HSCT) present lower progression and relapse rates, suppression of inflammatory activity, and a greater reduction in T2 lesions on MRI than those treated with disease-modifying therapies (DMTs). In summary, while SCT presents promise as a therapeutic option for MS, its deployment should be tailored to individual patient characteristics, disease stages, and responses.

The secretome of periodontal ligament stem cells from MS patients protects against EAE.

Manipulation of stem cells or stem cells-derived secretome has emerged as a novel alternative therapeutic option for multiple sclerosis (MS). Here we show that human periodontal ligament stem cells (hPDLSCs)-derived conditioned medium (hPDLSCs-CM) and purified exosomes/microvesicles (hPDLSCs-EMVs) obtained from Relapsing Remitting (RR)-MS patients and healthy donors block experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing anti-inflammatory and immunosuppressive effects in spinal cord and spleen, and reverse disease progression by restoring tissue integrity via remyelination in the spinal cord. We show that hPDLSCs-CM and hPDLSCs-EMVs reduce pro-inflammatory cytokines IL-17, IFN-γ, IL-1β, IL-6, TNF-α, and induce anti-inflammatory IL-10. In addition, apoptosis related STAT1, p53, Caspase 3, and Bax expressions were attenuated. Our findings unravel the immunosuppressive effects of hPDLSCs-CM and hPDLSCs-EMVs in EAE mice, and suggest simple alternative autologous source for patient-customized cell-free targeting treatment in MS patients.

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain

We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications.

Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific T-cell pathways. While the concept of "T-cell-specific therapy" implies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cell-selective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ∼75% in vitro and ∼60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis.

A TSPO ligand is protective in a mouse model of multiple sclerosis

Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids.

Dimethyl fumarate: a new oral treatment option for multiple sclerosis

Multiple Sclerosis (MS) is a slowly progressive, immunologically mediated disease of the CNS. The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis. There is a clear need for more effective, safe and at the same time orally available treatment options. Here we review the recently approved drug Dimethyl fumarate (DMF, Tecfidera®) as a new therapeutic option for MS and its role in context to the existing oral treatment options for MS. Dimethyl fumarate is the methyl ester of fumaric acid and has been claimed to possess immunomodulatory properties and is already in clinical use as Fumaderm for severe systemic psoriasis. In addition, Dimethyl fumarate was also shown to act on the blood-brain barrier and exert neuroprotective properties via activation of anti-oxidative pathways and displayed beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model mimicking many aspects of MS. Based on two global phase III studies. Dimethyl fumarate has been clinically proven to significantly reduce important measures of disease activity, including relapses and development of brain lesions, as well as to slow disability progression over time, while demonstrating a favourable safety and tolerability profile.

Immune Therapy of Multiple Sclerosis - Future Strategies

Baseline disease-modifying therapies (DMTs) for multiple sclerosis (MS) include three different preparations of interferon-beta (IFN-β) and glatiramer acetate (GA). These substances reduce relapse rates, side-effects are tolerated by most patients and - after more than 15 years of experience - the long-term safety profile for these drugs can be appraised as very good. In 2006, the therapeutic tool kit was augmented by the first monoclonal antibody, natalizumab, approved as monotherapy for treatment-refractory highly active MS. The restriction to these patient groups results from the rare, but fatal risk of JC virus-induced progressive multifocal leukoencephalopathy (PML). The first oral agent (fingolimod) was approved in 2010 for the United States and in 2011 for Europe. As a further option for therapy escalation the chemotherapeutic agent mitoxantrone is approved for non-responding relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS). The use of mitoxantrone is limited by severe cardiotoxicity and the risk of treatment related acute leukemia. However, despite the fact that therapeutic options for MS have significantly been widened over the past decade new treatment options and more convenient modes of application are needed to enhance efficacy and improve adherence to therapy. This article will review recent developments in MS treatments focusing on oral agents (cladribine, fingolimod, BG00012, teriflunomide and laquinimod) and novel monoclonal antibodies (alemtumzumab, daclizumab, ocrelizumab, ofatumumab).

Emerging Disease-Modifying Therapies in Multiple Sclerosis

The past two decades have seen tremendous expansion in therapeutic options for multiple sclerosis (MS). While the growing armamentarium of therapies provides physicians and patients an array of available options, it also brings in its wake the challenging responsibility of choosing the optimal therapy for an individual patient. In a newly diagnosed patient with relapsing disease, the current practice is to start one of the interferons (interferon-beta) or glatiramer acetate. With increasing experience and if there are no new safety concerns, use of fingolimod as a first-line agent in relapsing-remitting MS could expand. BG-12 appears to have a safety and efficacy profile that would make it a first-line agent, while tolerability would need to be considered. Teriflunomide is another oral agent that is under review by the US Food and Drug Administration and, apart from the pregnancy concerns, seems a potential first-line choice as well. For patients with high disease activity at onset or those refractory to current first-line agents, natalizumab and fingolimod are the two options considered most often at present. With the potential availability of alemtuzumab in the near future, that will provide an additional option considered highly efficacious. Its efficacy would have to be weighed carefully against its safety profile. Advances in genetics and biomarkers may allow the development of personalized medicine, and thus, the determination of the "best therapy" for an individual patient. Risk stratification strategies such as serum JC virus antibody status and pre-determination an individual's risk of autoimmune disease on alemtuzumab may facilitate early initiation of optimal therapies. Treatments for MS have come a long way and the future looks even more promising and will provide us with better and greater options in treating patients, meaning we can hope to see even less of an impact of the disease in the lives of patients with MS.

Epidemiological profile in multiple sclerosis patients, Uberaba, MG, Brazil

Dear Editor, We read with great interest the article published by Ribeiro SBF et al. (Arq Neuropsiquiatr 2011;69:184-187), about the epidemiological characteristics of patients with multiple sclerosis (MS) in the city of Uberaba-MG, Brazil. In this article, the authors comment on the similarity of most of the clinical and epidemiological features found in Uberaba to those presented in other samples in Brazil. However, when considering ethnicity, which in their study was predominantly Caucasian (85.71%), they cite the example of the city of Recife, where the incidence was predominantly in the black population (93.3%). They also mention the difficulties of ethnic classification in the Brazilian population, given the racial characteristics observed in our population. We agree that these difficulties exist but, nonetheless, we believe that ethnic traits need to be better studied in Brazil, with regard to the therapeutic options for multiple sclerosis. This can be seen from a study by Alves-Leon et al., in which they demonstrated the existence of heterogeneous phenotypes of HLA-DRB1*1501 in a population of healthy Brazilians that included both African descendants and white subjects. It is known that these alleles can negatively influence the therapeutic response to interferon. In another study, Brum et al. drew attention to the fact that HLA-DRB1 may exhibit behavior of either resistance or susceptibility in response to ethnic background and environmental factors. Brazil is a country of continental dimensions with a high degree of miscegenation. However, this miscegenation is variable with regard to demographic distribution. Ethnic characteristics need to be reviewed more carefully because surveys on the epidemiology of MS in some Brazilian cities have found that the rate of cases of MS among the black population was greater than that observed in other studies, especially in the cities of Rio de Janeiro (28%) and Cuiaba (26%). This implies that there is a need for regional and multicenter studies on MS in Brazil, especially in relation to the genetic susceptibility and environmental variables observed in a country with the dimensions of Brazil. Our congratulations to the authors.

Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis

Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%-15%) or relapsing-remitting (85%-90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia, chills and depression. Efficacy of IFN-β1b in relapsing-remitting MS is higher than that of IFN-β1a, and similar to the efficacy of glatiramer acetate. These facts promote IFN-β1b as one of the most important drugs in the spectrum of immunological therapies for this debilitating disease.

Intrathekale Baclofentherapie

This case report reviews the anesthesiological complications of intrathecal baclofen (ITB) therapy. An 11-year-old boy with spasticity and apallic syndrome needed general anesthesia for exchange of a baclofen pump but 2 h later he became increasingly hypothermic, hypotonic with bradycardy and dyspnea. The cause was an intra-operative bolus of ITB. Reduction of the baclofen administration rate caused disappearance of all symptoms without any residual effects. The ITB is an increasingly used therapeutic option for multiple sclerosis and cerebral palsy. Therefore, emergency personal and anesthesiologists must be aware of the possible side effects of this medication.

Immunotherapy of multiple sclerosis.

Multiple sclerosis (MS) is regarded as a prototypic inflammatory autoimmune central nervous system disorder causing neurological disability in young adults. Recommended basic immunomodulatory therapies of MS are currently interferon beta and glatiramer acetate. Both have proven to be clinically and paraclinically effective and clinical evidence suggests that treatment should be initiated as early as possible. However, despite the fact that therapeutic options for MS have significantly been widened over the past decade there is still tremendous activity in the search for new treatment options for MS. One important development in the field is reflected by the substantial number of promising results for oral therapies. Various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. It is hoped that these oral therapies for MS further broaden our armament for MS therapy.

Blood Brain Barrier Compromise with Endothelial Inflammation may Lead to Autoimmune Loss of Myelin during Multiple Sclerosis

Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammation and demyelination within the central nervous system. The mechanism that triggers the disease remains elusive. However, recent findings may indicate that multiple sclerosis, at its source, could be a hemodynamic disorder. It has been found that multiple sclerosis patients exhibit significant stenoses in extracranial veins draining the central nervous system (in azygous and internal jugular veins), which are associated with significant pressure gradients measured across strictures. Such anatomic venous abnormalities were not found in the control group of healthy subjects. In this review, it is hypothesized that pathological refluxing venous flow in the cerebral and spinal veins increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the cerebrovascular endothelium. This, in turn, could lead to the increased permeability of the blood-brain barrier. Inflamed and activated endothelium could secrete proinflammatory cytokines, including GM-CSF and TGF-beta In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells. Consequently, a potential therapeutic option for multiple sclerosis could be pharmacotherapy with either substances that strengthen the tight-junctions barrier, or with agents that reduce the expression of adhesion molecules. In addition, surgical correction could be an option in some anatomical variants of pathologic venous outflow. We are optimistic that a hemodynamic approach to the multiple sclerosis pathogenesis can open a new chapter of investigations and treatment of this debilitating neurologic disease.

Luteolin as a therapeutic option for multiple sclerosis

Multiple sclerosis (MS) remains without an effective treatment in spite of intense research efforts. Interferon-beta (IFN-β) reduces duration and severity of symptoms in many relapsing-remitting MS patients, but its mechanism of action is still not well understood. Moreover, IFN-β and other available treatments must be given parenterally and have a variety of adverse effects. Certain naturally occurring flavonoids, such as luteolin, have anti-oxidant and anti-inflammatory effects, including inhibition of activated peripheral blood leukocytes from MS patients. Luteolin also inhibits mast cells, as well as mast cell-dependent T cell activation, recently implicated in MS pathogenesis. Moreover, luteolin and structurally similar flavonoids can inhibit experimental allergic allergic encephalomyelitis (EAE), an animal model of MS in rodents. An appropriate luteolin formulation that permits sufficient absorption and reduces its metabolism could be a useful adjuvant to IFN-β for MS therapy.

Promising treatments of tomorrow for multiple sclerosis

The therapeutic options for multiple sclerosis are rapidly expanding. What was once seen as a disease with little hope for treatment is now a target of rapid drug development. Current therapies have demonstrated efficacy in limiting the impact of the disease, but none is fully effective in all patients. However, promising new treatments are on the horizon. In this review we will discuss potential novel immunomodulating drugs that are in advanced stages of investigation; these drugs include monoclonal antibodies, chimeric molecules, and oral therapies. The use of hematopoietic stem cells will also be discussed and, in addition, we will look farther ahead at possible novel targets for the development of new immunomodulatory or neuroprotective pharmaceuticals.

Review: Innovative monoclonal antibody therapies in multiple sclerosis

The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS), especially for relapsing-remitting disease courses. In particular, the application of monoclonal antibodies provide innovative approaches allowing for blocking or depleting specific molecular targets, which are of interest in the pathogenesis of MS. While natalizumab received approval by the US Food and Drug Administration and the European Medicines Agency in 2006 as the first monoclonal antibody in MS therapy, rituximab, alemtuzumab, and daclizumab were successfully tested for relapsing-remitting MS in small cohorts in the meantime. Here, we review the data available from these recent phase II trials and at the same time critically discuss possible pitfalls which may be relevant for clinical practice. The results of these studies may not only broaden our therapeutic options in the near future, but also provide new insights into disease pathogenesis.

FTY720 (Fingolimod) as a new therapeutic option for multiple sclerosis

All currently available therapeutic options for multiple sclerosis have to be administered parenterally. Several oral substances are currently in the late clinical development stage. One of them, FTY720 (also known as fingolimod) is highlighted in this review. The biological effects of FTY720 are presented as well as animal data and first clinical data from a phase II trial in multiple sclerosis patients. The effects of FTY720 are based on an innovative approach and apparently target several key elements in the pathogenesis of multiple sclerosis. The first clinical data with FTY720 show very promising results, with a relapse reduction of over 50% compared to placebo and an acceptable safety profile. These results currently await confirmation in two international phase III studies which are recruiting patients worldwide.