Multiple sclerosis: new treatment trials and emerging therapeutic targets

DeAngelis, Tracy M.; Lublin, Fred

doi:10.1097/wco.0b013e328300c70d

Cited by 26 publications

(18 citation statements)

References 38 publications

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“…While all MS therapies have distinct mechanisms of actions, most have a limited efficacy rate of between 30–60% or are associated with significant side-effects or toxicity (e.g. natalizumab, mitoxantrone) [4], [5], [6]. Thus, there is a great need for alternative therapies with greater efficacy, which target forms of MS for which there are no effective treatments, or that cause minimal side effects when chronically administered.…”

Section: Introductionmentioning

confidence: 99%

Treatment with the Antipsychotic Agent, Risperidone, Reduces Disease Severity in Experimental Autoimmune Encephalomyelitis

et al. 2014

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Recent studies have demonstrated that atypical antipsychotic agents, which are known to antagonize dopamine D2 and serotonin 5-HT2a receptors, have immunomodulatory properties. Given the potential of these drugs to modulate the immune system both peripherally and within the central nervous system, we investigated the ability of the atypical anti-psychotic agent, risperidone, to modify disease in the animal model of multiple sclerosis (MS)4, experimental autoimune encephalomyelitis (EAE). We found that chronic oral administration of risperidone dose-dependently reduced the severity of disease and decreased both the size and number of spinal cord lesions. Furthermore, risperidone treatment substantially reduced antigen-specific interleukin (IL)-17a, IL-2, and IL-4 but not interferon (IFN)-γ production by splenocytes at peak disease and using an in vitro model, we show that treatment of macrophages with risperidone alters their ability to bias naïve T cells. Another atypical antipsychotic agent, clozapine, showed a similar ability to modify macrophages in vitro and to reduce disease in the EAE model but this effect was not due to antagonism of the type 1 or type 2 dopamine receptors alone. Finally, we found that while risperidone treatment had little effect on the in vivo activation of splenic macrophages during EAE, it significantly reduced the activation of microglia and macrophages in the central nervous system. Together these studies indicate that atypical antipsychotic agents like risperidone are effective immunomodulatory agents with the potential to treat immune-mediated diseases such as MS.

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Section: Introductionmentioning

confidence: 99%

Treatment with the Antipsychotic Agent, Risperidone, Reduces Disease Severity in Experimental Autoimmune Encephalomyelitis

et al. 2014

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“…In conditions such as multiple sclerosis, therapies for clinical exacerbation are limited. Targeting blood-brain barrier disruption may effectively limit tissue damage and relapse severity (DeAngelis and Lublin, 2008).…”

Section: Introductionmentioning

confidence: 99%

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

Chapouly

Argaw

Horng

et al. 2015

Brain

147

136

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*These authors contributed equally to this work.In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-D-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-D-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

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“…As such, an agent that targets B cells, such as the anti-CD20 mAb rituximab [38], offers a logical approach to MS therapy [39]. Rituximab demonstrated a rapid and sustained improvement in disease activity (both clinical and MRI outcomes) in an open-labeled Phase I trial of patients with RRMS [40], and a small doubleblind Phase II trial, HERMES [41].…”

Section: Anti-cd20 Agentsmentioning

confidence: 99%

Emerging Strategies For the Treatment of Multiple Sclerosis

Sand

Krieger

2012

Future Neurol.

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Despite extraordinary advances in the field of neuroimmunology, ideal treatment for patients with multiple sclerosis remains an unmet need. Existing treatments are only partially effective in preventing multiple sclerosis relapses, have a limited impact on the accrual of disability, have not been effective in progressive forms of the disease, and treatment remains preventive rather than restorative. This review provides an overview of emerging therapies and targets, and incorporates strategies for two different approaches to multiple sclerosis: prevention, through immune modulation; and repair, through neuroprotection and remyelination. Agents at all stages of development, from late-stage clinical trials of BG-12, teriflunomide, alemtuzumab, daclizumab and anti-CD20 agents, to novel approaches in preclinical testing, are discussed.

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Multiple sclerosis: new treatment trials and emerging therapeutic targets

Cited by 26 publications

References 38 publications

Treatment with the Antipsychotic Agent, Risperidone, Reduces Disease Severity in Experimental Autoimmune Encephalomyelitis

Treatment with the Antipsychotic Agent, Risperidone, Reduces Disease Severity in Experimental Autoimmune Encephalomyelitis

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

Emerging Strategies For the Treatment of Multiple Sclerosis

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