Multiple Sclerosis Therapeutics Research Articles

Lymphocyte Counts and Multiple Sclerosis Therapeutics: Between Mechanisms of Action and Treatment-Limiting Side Effects

Although the detailed pathogenesis of multiple sclerosis (MS) is not completely understood, a broad range of disease-modifying therapies (DMTs) are available. A common side effect of nearly every MS therapeutic agent is lymphopenia, which can be both beneficial and, in some cases, treatment-limiting. A sound knowledge of the underlying mechanism of action of the selected agent is required in order to understand treatment-associated changes in white blood cell counts, as well as monitoring consequences. This review is a comprehensive summary of the currently available DMTs with regard to their effects on lymphocyte count. In the first part, we describe important general information about the role of lymphocytes in the course of MS and the essentials of lymphopenic states. In the second part, we introduce the different DMTs according to their underlying mechanism of action, summarizing recommendations for lymphocyte monitoring and definitions of lymphocyte thresholds for different therapeutic regimens.

Gut Microbiome as Potential Therapeutics in Multiple Sclerosis

Gut Microbiome as Potential Therapeutics in Multiple Sclerosis

Proinflammatory CD20+ T Cells are Differentially Affected by Multiple Sclerosis Therapeutics.

The frequency of CD20+ T cells was reported to be increased in several inflammatory conditions. We report that in patients with multiple sclerosis (MS), CD20+ T cells display a distinct proinflammatory phenotype with pathogenic properties. Anti-CD20 treatment virtually extinguished CD20+ T cells, which might explain its broad effectiveness. Dimethyl fumarate dampened activity of differentiated CD20+ T cells, whereas fingolimod reduced their abundance only as part of its overall T cell suppressive capacity. Natalizumab increased the frequency of CD20+ effector T cells. Widely used MS therapeutics affect this proinflammatory T cell subset with assumed pathogenic potential in a surprisingly differential manner. ANN NEUROL 2021 ANN NEUROL 2021;90:834-839.

Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling.

Cyclotides are plant-derived disulfide-rich peptides comprising a cyclic cystine knot, which confers remarkable stability against thermal, proteolytic, and chemical degradation. They represent an emerging class of G protein-coupled receptor (GPCR) ligands. In this study, utilizing a screening approach of plant extracts and pharmacological analysis we identified cyclotides from Carapichea ipecacuanha to be ligands of the κ-opioid receptor (KOR), an attractive target for developing analgesics with reduced side effects and therapeutics for multiple sclerosis (MS). This prompted us to verify whether [T20K]kalata B1, a cyclotide in clinical development for the treatment of MS, is able to modulate KOR signaling. T20K bound to and fully activated KOR in the low μM range. We then explored the ability of T20K to allosterically modulate KOR. Co-incubation of T20K with KOR ligands resulted in positive allosteric modulation in functional cAMP assays by altering either the efficacy of dynorphin A1–13 or the potency and efficacy of U50,488 (a selective KOR agonist), respectively. In addition, T20K increased the basal response upon cotreatment with U50,488. In the bioluminescence resonance energy transfer assay T20K negatively modulated the efficacy of U50,488. This study identifies cyclotides capable of modulating KOR and highlights the potential of plant-derived peptides as an opportunity to develop cyclotide-based KOR modulators.

Chronic Demyelination and Axonal Degeneration in Multiple Sclerosis: Pathogenesis and Therapeutic Implications.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). Inflammatory attacks in MS lead to both demyelination and axonal damage. However, due to incomplete remyelination most MS lesions remain chronically demyelinated. In parallel, there is axonal degeneration in the CNS of MS patients, contributing to progressive disability. There are currently no approved therapies that adequately restore myelin or protect axons from degeneration. In this review, we will discuss the pathophysiology of axonal loss and chronic demyelination in MS and how understanding this pathophysiology is leading to the development of new MS therapeutics. Ongoing research into the function of oligodendrocytes and myelin has revealed the importance of their relationship with neuronal health. Demyelination in MS leads to a number of pathophysiologic changes contributing to axonal generation. Among these are mitochondrial dysfunction, persistent neuroinflammation, and the effects of reactive oxygen and nitrogen species. With this information, we review currently approved and investigational therapies designed to restore lost or damaged myelin and protect against neuronal degeneration. The development of therapies to restore lost myelin and protect neurons is a promising avenue of investigation for the benefit of patients with MS.

Multifaceted involvement of microglia in gray matter pathology in multiple sclerosis.

In the inflammatory demyelinating neurodegenerative disease multiple sclerosis (MS), there is increasing interest in gray matter pathology, as neuronal loss and cortical atrophy correlate with disability and disease progression, and MS therapeutics fail to significantly slow or stop neurodegeneration. Microglia, the central nervous system (CNS)-resident macrophages, are extensively involved in white matter MS pathology, but are also implicated in gray matter pathology, similar to other neurodegenerative diseases, for which there is synaptic, axonal, and neuronal degeneration. Microglia display regional heterogeneity within the CNS, which reflects their highly plastic nature and their ability to deliver context-dependent responses tailored to the demands of their microenvironment. Therefore, microglial roles in the MS gray matter in part reflect and in part diverge from those in the white matter. The present review summarizes current knowledge of microglial involvement in gray matter changes in MS, in demyelination, synaptic damage, and neurodegeneration, with evidence implicating microglia in pathology, neuroprotection, and repair. As our understanding of microglial physiology and pathophysiology increases, we describe how we are moving toward potential therapeutic applications in MS, harnessing microglia to protect and regenerate the CNS.

New therapeutics in multiple sclerosis and neuromyelitis optica

New therapeutics in multiple sclerosis and neuromyelitis optica

Next-generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells.

ObjectivesBruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecule inhibitor of BTK.MethodsBIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial.Results In vitro, BIIB091 potently inhibited BTK‐dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell‐targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long‐lived complexes with BTK with t 1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B‐cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B‐cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing.ConclusionPharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.

Uncovering New Challenges in Targeting Glycolysis to Treat Th17 Cell-Mediated Autoimmunity.

Targeting glycolysis in T helper 17 (Th17) cells presents an attractive opportunity to treat Th17 cell-mediated autoimmune diseases such as multiple sclerosis (MS). Pyruvate kinase isoform 2 (PKM2) is a glycolytic enzyme expressed in T cells infiltrating the central nervous system in a mouse model of MS, suggesting PKM2 modulation could provide a new avenue for MS therapeutics. In a recent article in Science Signaling, Seki et al. show that pharmacological modulation of PKM2 alters but does not ameliorate disease in a mouse model of MS. These results warrant further consideration of PKM2 modulators to treat Th17 cell-mediated autoimmunity.

Role of B Cells in Multiple Sclerosis and Related Disorders.

The success of clinical trials of selective B-cell depletion in patients with relapsing multiple sclerosis (MS) and primary progressive MS has led to a conceptual shift in the understanding of MS pathogenesis, away from the classical model in which T cells were the sole central actors and toward a more complex paradigm with B cells having an essential role in both the inflammatory and neurodegenerative components of the disease process. The role of B cells in MS was selected as the topic of the 27th Annual Meeting of the European Charcot Foundation. Results of the meeting are presented in this concise review, which recaps current concepts underlying the biology and therapeutic rationale behind B-cell-directed therapeutics in MS, and proposes strategies to optimize the use of existing anti-B-cell treatments and provide future directions for research in this area. ANN NEUROL 2021;89:13-23.

The role of TH17 cells in multiple sclerosis: Therapeutic implications.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where immunopathology is thought to be mediated by myelin-reactive CD4+ T helper (TH) cells. The TH cells most commonly implicated in the pathogenesis of the disease are of TH1 and TH17 lineage, which are defined by the production of interferon-γ and interleukin-17, respectively. Moreover, there is emerging evidence for the involvement of TH17.1 cells, which share the hallmarks of TH1 and TH17 subsets. In this review, we summarise current knowledge about the potential role of TH17 subsets in the initiation and progression of the disease and put a focus on their response to approved immunomodulatory MS drugs. In this regard, TH17 cells are abundant in peripheral blood, cerebrospinal fluid and brain lesions of MS patients, and their counts and inflammatory mediators are further increased during relapses. Fingolimod and alemtuzumab induce a paramount decrease in central memory T cells, which harbour the majority of peripheral TH17 cells, while the efficacy of natalizumab, dimethyl fumarate and importantly hematopoietic stem cell therapy correlates with TH17.1 cell inhibition. Interestingly, also CD20 antibodies target highly inflammatory TH cells and hamper TH17 differentiation by IL-6 reductions. Moreover, recovery rates of TH cells best correlate with long-term efficacy after therapeutical immunodepletion. We conclude that central memory TH17.1 cells play a pivotal role in MS pathogenesis and they represent a major target of MS therapeutics.

Differential Effects of MS Therapeutics on B Cells-Implications for Their Use and Failure in AQP4-Positive NMOSD Patients.

B cells are considered major contributors to multiple sclerosis (MS) pathophysiology. While lately approved disease-modifying drugs like ocrelizumab deplete B cells directly, most MS medications were not primarily designed to target B cells. Here, we review the current understanding how approved MS medications affect peripheral B lymphocytes in humans. These highly contrasting effects are of substantial importance when considering these drugs as therapy for neuromyelitis optica spectrum disorders (NMOSD), a frequent differential diagnosis to MS, which is considered being a primarily B cell- and antibody-driven diseases. Data indicates that MS medications, which deplete B cells or induce an anti-inflammatory phenotype of the remaining ones, were effective and safe in aquaporin-4 antibody positive NMOSD. In contrast, drugs such as natalizumab and interferon-β, which lead to activation and accumulation of B cells in the peripheral blood, lack efficacy or even induce catastrophic disease activity in NMOSD. Hence, we conclude that the differential effect of MS drugs on B cells is one potential parameter determining the therapeutic efficacy or failure in antibody-dependent diseases like seropositive NMOSD.

Frailty in ageing persons with multiple sclerosis

Background: Recent progress in multiple sclerosis (MS) management has contributed to a greater life expectancy in persons with MS. Ageing with MS comes with unique challenges and bears the potential to greatly affect quality of life and socioeconomic burden. Objectives: To compare frailty in ageing persons with multiple sclerosis (pwMS) and controls; to correlate frailty with MS clinical characteristics. Methods: PwMS and controls over 50 years old were recruited in a cross-sectional study. Two validated frailty measures were assessed: the frailty index and the Fried’s phenotype. Several multiple linear regressions accounting for demographic and clinical characteristics were performed. Results: Eighty pwMS (57 females, mean age 58.5 ± 6 years old) and 37 controls (24 females, mean age 61 ± 6.5 years old) were recruited. Multivariable analysis identified significantly higher frailty index in pwMS (0.21 ± 0.12 vs 0.11 ± 0.08, p < 0.0001). Similarly, according to Fried’s phenotype, a significantly higher percentage of pwMS were frail compared to controls (28% vs 8%). In pwMS, frailty index was independently associated with expanded disability status scale (EDSS), comorbidities, education level and disease duration. Conclusion: Our results suggest that frailty can be routinely assessed in pwMS. Increased frailty in MS patients suggests that, along with MS therapeutics, a tailored multidisciplinary approach of ageing pwMS is needed.

Feast or famine in multiple sclerosis therapeutics.

Feast or famine in multiple sclerosis therapeutics.

Reliability and validity of a novel device for quantifying ankle dorsiflexion force in persons with multiple sclerosis

BackgroundWith emerging treatment modalities and therapeutics for Multiple Sclerosis (MS), there is a critical need for improved measures of disability. Routine clinical practice and trials will benefit from devices that are capable of objectively quantifying muscle strength/weakness. We have developed a device for measuring Tibialis Anterior (TA) force that is both objective and easy to use - the Rapid Objective Quantification - TA (ROQ-TA). The purpose of this study was to determine the reliability and validity of the ROQ-TA versus Manual Muscle Testing and Isokinetic Dynamometry (IKD) for evaluating TA force in persons with MS (PwMS). MethodsAnkle dorsiflexion of 20 PwMS was assessed by three modalities: ROQ-TA, MMT, and IKD over 2 testing sessions. ICC(2,1) values and Bland-Altman plots were used to assess reliability and validity of the ROQ-TA. ResultsThe ICC(2,1) for reliability for the ROQ-TA was found to be 0.884 (0.690–0.957) while the IKD produced a similar ICC(2,1) of 0.919 (0.784–0.970). The mean difference between the two sessions for the ROQ-TA was -6.4 N with limits of agreement of 42.5 to -55.4 N as inferred by the Bland-Altman plots. With respect to validity, the ROQ-TA versus IKD yielded similar values for both sessions- the mean bias was 9.3 N (SE range: -3.4 to 22 N) for session 1 and 9.9 N for session 2 (SE range: -3.2 to 23.0 N). The ICC(2,1) values between the two devices were in moderate agreement - session 1: 0.579 (-0.125–0.843) and session 2: 0.490 (-0.363–0.809). ConclusionThe ROQ-TA is a valid and highly reliable device to test dorsiflexion force in PwMS.

Epigenetics in Multiple Sclerosis.

Multiple sclerosis (MS) is an aggravating autoimmune disease that cripples young patients slowly with physical, sensory and cognitive deficits. The break of self-tolerance to neuronal antigens is the key to the pathogenesis of MS, with autoreactive T cells causing demyelination that subsequently leads to inflammation-mediated neurodegenerative events in the central nervous system. The exact etiology of MS remains elusive; however, the interplay of genetic and environmental factors contributes to disease development and progression. Given that genetic variation only accounts for a fraction of risk for MS, extrinsic risk factors including smoking, infection and lack of vitamin D or sunshine, which cause changes in gene expression, contribute to disease development through epigenetic regulation. To date, there is a growing body of scientific evidence to support the important roles of epigenetic processes in MS. In this chapter, the three main layers of epigenetic regulatory mechanisms, namely DNA methylation, histone modification and microRNA-mediated gene regulation, will be discussed, with a particular focus on the role of epigenetics on dysregulated immune responses and neurodegenerative events in MS. Also, the potential for epigenetic modifiers as biomarkers and therapeutics for MS will be reviewed.

Immunological Aspects of Approved MS Therapeutics.

Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies.

Multiple sclerosis (MS) presenting in the pediatric years can lead to landmark disability levels younger in life than adult onset MS and so therefore early and effective treatment remains paramount for long-term outcomes. The goals of MS therapeutics in adults have widened to address multiple mechanisms: anti-inflammatory, neuroprotective, and myelin repair, yet the optimal paradigm for MS therapies in the pediatric population is not known. Pediatric onset MS add complexities due to the ongoing development of the central nervous system and the immune system. Clinical trials have led to an increasing number of pharmaceutical therapies for adult onset MS (AOMS), one POMS randomized controlled trial is completed and other trials are ongoing, yet due to the low prevalence of POMS, the dynamic landscape and risk management of the MS disease modifying therapies (DMT) it remains more difficult to complete trials in POMS. There is consensus that controlled clinical trials leading to appropriate and safe therapies for POMS are important for a multitude of reasons that include unique pediatric pharmacokinetics, short and long-term safety, developmental issues, clinical benefits, and regulatory approval. This review will focus on new treatment goals, paradigm, strategies, monitoring, compliance, and products in the long-term treatment of POMS. The discussion will focus on these new concepts and the published data related to DMT use in POMS. This review provides significant insight into new concepts of treatment goals and current approaches to enhance the lives of the POMS patients now and in the future.

Dopaminergic Therapeutics in Multiple Sclerosis: Focus on Th17-Cell Functions.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with an autoimmune mechanism of development. Currently, one of the most promising directions in the study of MS pathogenesis are the neuroimmune interactions. Dopamine is one of the key neurotransmitters in CNS. Furthermore, dopamine is a direct mediator of interactions between the immune and nervous systems and can influence MS pathogenesis by modulating immune cells activity and cytokine production. Recent studies have shown that dopamine can enhance or inhibit the functions of innate and adaptive immune system, depending on the activation of different dopaminergic receptors, and can therefore influence the course of experimental autoimmune encephalomyelitis (EAE) and MS. In this review, we discuss putative dopaminergic therapeutics in EAE and MS with focus on Th17-cells, which are thought to play crucial role in MS pathogenesis. We suggest that targeting dopaminergic receptors could be explored as a new kind of disease-modifying treatment of MS. Graphical Abstract.

Therapeutic Applications of Monoclonal Antibodies in Multiple Sclerosis

Despite the various therapies available, the use of monoclonal antibodies is a highly specific approach that has only recently been of interest to researchers. The properties of antibodies have led to their use in the treatment of various diseases, including cancer, Alzheimer's disease, diabetes and multiple sclerosis (MS). MS, a chronic inflammatory disease, occurs commonly in young adults. The disease is one of the attractive options for monoclonal antibody therapy because it has no definitive drug for its treatment. Antibodies, by targeting different molecules, have different mechanisms to improve the disease. Treatment with monoclonal antibody has culminated in a clear divergence in paradigm and concentration in MS therapeutics. Application of monoclonal antibody in early inflammatory phases can inhibit or postpone the disability in MS subjects. Ocrelizumab and daclizumab are currently under investigation by late phase III trials, and some other monoclonal antibodies are in the early stages of clinical trials. Monoclonal antibodies are of special structural features (including chimeric, humanized, or fully humanized) as well as specific targets (such as stimulation of signal transduction by binding to receptors, blocking interactions, antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity), thus providing various mechanisms of actions during MS therapy. In the present paper, we reviewed different monoclonal antibodies used in MS, their mechanism of action and theirs target molecules.