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 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 Ozanimod to Treat Relapsing Forms of Multiple Sclerosis: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

2020 ◽  
Vol 12 (3) ◽  
pp. 89-108
Author(s):  
Grace Lassiter ◽  
Carlie Melancon ◽  
Tyler Rooney ◽  
Anne-Marie Murat ◽  
Jessica S. Kaye ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Drug Efficacy ◽  
Receptor Modulator ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
The Us ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Us Fda ◽  
Reversible Encephalopathy

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.

scholarly journals Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 227
Author(s):  
Stanley Cohan ◽  
Elisabeth Lucassen ◽  
Kyle Smoot ◽  
Justine Brink ◽  
Chiayi Chen
Keyword(s):  
Multiple Sclerosis ◽  
G Protein ◽  
Cell Types ◽  
Protective Effects ◽  
Preclinical Research ◽  
Pharmacological Agents ◽  
Inflammatory Damage ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Lymphocyte Egress

Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS.

FTY720 on the way from the base camp to the summit of the mountain: relevance for remyelination

2012 ◽  
Vol 18 (3) ◽  
pp. 258-263 ◽  
Author(s):  
M Kipp ◽  
S Amor
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Oral Disease ◽  
S1p Receptors ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

FTY720 (fingolimod; Gilenya®), a sphingosine 1-phosphate (S1P) receptor modulator, is the first oral disease-modifying therapy to be approved for the treatment of relapsing–remitting multiple sclerosis. FTY720 is rapidly converted in vivo to the active S-fingolimod-phosphate, which binds to S1P receptors. This action inhibits egress of lymphocytes from the lymph nodes, preventing entry into the blood and thus infiltration into the central nervous system. More recent studies, however, convincingly show that FTY720 crosses the blood–brain barrier, where it is thought to act on S1P receptors on cells within the central nervous system, such as astrocytes, oligodendrocytes or microglia. Here we discuss the evidence showing that FTY720 also plays a role in remyelination and repair within the brain. While the mechanisms of action still require firm elucidation, it is clear that FTY720 could also be reparative, extending its therapeutic potential for multiple sclerosis.

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 Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses

2021 ◽  
Vol 22 (15) ◽  
pp. 7864
Author(s):  
Bhakta Prasad Gaire ◽  
Ji-Woong Choi
Keyword(s):  
Multiple Sclerosis ◽  
Cerebral Ischemia ◽  
Neurological Diseases ◽  
Glial Activation ◽  
Lpa Receptor ◽  
Cord Injury ◽  
Lpa Receptors ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Comprehensive Framework

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.

scholarly journals Does Siponimod Exert Direct Effects in the Central Nervous System?

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1771 ◽  
Author(s):  
Markus Kipp
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Direct Interaction ◽  
Active Role ◽  
Progressive Multiple Sclerosis ◽  
Receptor Subtypes ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

Sign in / Sign up

Export Citation Format

Share Document