scholarly journals Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis

CNS Drugs ◽  
2015 ◽  
Vol 29 (7) ◽  
pp. 565-575 ◽  
Author(s):  
Adnan M. Subei ◽  
Jeffrey A. Cohen
Keyword(s):  
Multiple Sclerosis ◽  
Sphingosine 1 Phosphate ◽  
Receptor Modulators

scholarly journals Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis

2018 ◽  
Vol 13 (1) ◽  
pp. 25 ◽  
Author(s):  
Patrick Vermersch
Keyword(s):  
Multiple Sclerosis ◽  
Oral Disease ◽  
Receptor Subtypes ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
S1p Receptor ◽  
Phase Ii And Iii ◽  
Receptor Modulators ◽  
Term Data

The introduction of oral disease modifying therapies has transformed the treatment landscape for patients with multiple sclerosis (MS). Fingolimod (Gilenya®, Novartis, Basel, Switzerland), the first oral therapy to be approved, has demonstrated clinical efficacy as a result of modulation of subtype 1 sphingosine-1-phosphate (S1P1) receptors. This leads to retention of lymphocytes in the lymph nodes, preventing their entry into the central nervous system. However, fingolimod can cause adverse effects as a result of its interaction with other S1P receptor subtypes, which are expressed in numerous tissues, including cardiac myocytes. More selective S1P receptor agents are currently in phase II and III clinical development. Siponimod, ozanimod, ponesimod and amiselimod have demonstrated efficacy with improved safety profiles compared with fingolimod. While more long-term data are needed, these selective S1P receptor modulators appear to be promising options for the treatment of MS and other disorders associated with autoimmunity and inflammation.

scholarly journals Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders

2019 ◽  
Vol 59 (1) ◽  
pp. 149-170 ◽  
Author(s):  
Jerold Chun ◽  
Yasuyuki Kihara ◽  
Deepa Jonnalagadda ◽  
Victoria A. Blaho
Keyword(s):  
Multiple Sclerosis ◽  
Drug Targets ◽  
Science Studies ◽  
Lessons Learned ◽  
Fungal Metabolites ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Disease Stages ◽  
Receptor Modulators

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration–approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.

scholarly journals Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis

2017 ◽  
Vol 14 (4) ◽  
pp. 859-873 ◽  
Author(s):  
Burhan Z. Chaudhry ◽  
Jeffrey A. Cohen ◽  
Devon S. Conway
Keyword(s):  
Multiple Sclerosis ◽  
Sphingosine 1 Phosphate ◽  
Receptor Modulators

scholarly journals Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1290 ◽  
Author(s):  
Alessandra Musella ◽  
Antonietta Gentile ◽  
Livia Guadalupi ◽  
Francesca Romana Rizzo ◽  
Francesca De Vito ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ex Vivo ◽  
The United States ◽  
Neuroprotective Effects ◽  
Local Inflammatory Response ◽  
Electrophysiological Studies ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Receptor Modulators

Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.

scholarly journals Clinical features and outcomes of COVID-19 despite SARS-CoV-2 vaccination in people with multiple sclerosis

2021 ◽  
Vol 7 (4) ◽  
pp. 205521732110571
Author(s):  
Deja R Rose ◽  
Ahmad Z Mahadeen ◽  
Alise K Carlson ◽  
Sarah M Planchon ◽  
Jennifer Sedlak ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
At Risk ◽  
Cleveland Clinic ◽  
Serological Response ◽  
Limited Data ◽  
Disease Modifying Therapy ◽  
Sphingosine 1 Phosphate ◽  
Disease Modifying ◽  
Anti Cd20 ◽  
Receptor Modulators

Background Several studies have demonstrated reduced serological response to vaccines in patients treated with anti-CD20 agents. However, limited data exist surrounding the clinical effect of disease modifying therapy (DMT) use on vaccine efficacy. Objectives To investigate breakthrough coronavirus disease 2019 (COVID-19) in vaccinated people with multiple sclerosis (PwMS) on DMT. Methods PwMS on DMT diagnosed with COVID-19 after full vaccination were identified from an existing Cleveland Clinic COVID-19 registry, supplemented by provider-identified cases. Demographics, disease history, DMTs, comorbidities, exposures, vaccination status, and COVID-19 outcomes were confirmed by review of the electronic medical record. Results Thirteen (3.8%) of 344 fully vaccinated people with multiple sclerosis on disease modifying therapy were diagnosed with COVID-19 after vaccination. Ten patients (76.9%) were on an anti-CD20 therapy, the remaining 3 (23.1%) on fingolimod. Only 2 patients (15.4%), both on anti-CD20 therapy, required hospitalization and steroid treatment. Neither required Intensive Care Unit admission. Conclusion Patients treated with anti-CD20 agents and sphingosine 1-phosphate receptor modulators may still be at risk for COVID-19 despite vaccination. While still at risk for hospitalization, intubation and death from COVID-19 appear rare. Larger studies analyzing how this may differ in the setting of emerging variants are needed.

scholarly journals Immunoglobulin G immune response to SARS-CoV-2 vaccination in people living with multiple sclerosis within Multiple Sclerosis Partners Advancing Technology and Health Solutions

2022 ◽  
pp. 135245852110613
Author(s):  
Jeffrey A Cohen ◽  
Robert A Bermel ◽  
Cynthia I Grossman ◽  
Carrie M Hersh ◽  
Megan Hyland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immunoglobulin G ◽  
Post Vaccination ◽  
Vaccination Response ◽  
Disease Modifying Therapies ◽  
Igg Index ◽  
Sphingosine 1 Phosphate ◽  
Anti Cd20 ◽  
The Impact ◽  
Receptor Modulators

Background: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS-CoV-2 vaccination response is uncertain. Methods: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS-CoV-2 immunoglobulin G (IgG) response. Results: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including the no DMT group. Conclusion: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG response is preserved with other DMTs.

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