Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices.
Veronique E. Miron,Samuel K. Ludwin,Peter J. Darlington,Andrew A. Jarjour,Andrew A. Jarjour,Betty Soliven,Timothy E. Kennedy,Jack P. Antel +7 more
TLDR
Data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain.Abstract:
Remyelination, which occurs subsequent to demyelination, contributes to functional recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated into myelinating cells. Therapeutics that impact remyelination in the CNS could be critical determinants of long-term functional outcome in multiple sclerosis (MS). Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier. Previous studies using isolated dissociated cultures indicate that neural cells express S1P receptors and respond to receptor engagement. Our objective was to assess the effects of fingolimod on myelin-related processes within a multicellular environment that maintains physiological cell-cell interactions, using organotypic cerebellar slice cultures. Fingolimod treatment had no impact on myelin under basal conditions. Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes, while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein. The number of phagocytosing microglia was not increased by fingolimod. Using S1P receptor specific agonists and antagonists, we determined that fingolimod-induced effects on remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas enhanced microgliosis was mediated through S1P1 and S1P5. Taken together, these data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain.read more
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Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Volker Brinkmann,Andreas Billich,Thomas Baumruker,Peter Heining,Robert Schmouder,Gordon Francis,Shreeram Aradhye,Pascale Burtin +7 more
TL;DR: The discovery and development of fingolimod is described, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.
Journal ArticleDOI
An update on the biology of sphingosine 1-phosphate receptors.
Victoria A. Blaho,Timothy Hla +1 more
TL;DR: This review will focus on the most recent advances in S1PRs, as they become attractive therapeutic targets in several diseases, such as chronic inflammatory pathologies, autoimmunity, and cancer.
Journal ArticleDOI
Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial
Fred D. Lublin,David Miller,Mark S. Freedman,Bruce A.C. Cree,Jerry S. Wolinsky,Howard L. Weiner,Catherine Lubetzki,Hans-Peter Hartung,Xavier Montalban,Bernard M. J. Uitdehaag,Martin Merschhemke,Bingbing Li,Norman Putzki,Fonda Liu,Dieter A. Häring,Ludwig Kappos +15 more
TL;DR: A novel primary composite endpoint was used based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years.
Journal ArticleDOI
An update on sphingosine-1-phosphate and other sphingolipid mediators.
Henrik Fyrst,Julie D. Saba +1 more
TL;DR: Preclinical and clinical investigations using pharmacological agents that target sphingosine-1-phosphate, its receptors and the enzymes required for its biosynthesis and degradation demonstrate the promise and potential risks of modulating sphingOSine- 1- phosphate signaling in treatment strategies for autoimmunity, cancer, cardiovascular disease and other pathological conditions.
Journal ArticleDOI
Fingolimod for Multiple Sclerosis
Daniel Pelletier,David A. Hafler +1 more
TL;DR: A 37-year-old man with multiple sclerosis has recurrent disease activity despite several previous therapies, and treatment with fingolimod is recommended.
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Journal ArticleDOI
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Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination
Corinna Lappe-Siefke,Sandra Goebbels,Michel Gravel,Eva Nicksch,John H.S. Lee,Peter E. Braun,Ian R. Griffiths,Klaus-Armin Nave +7 more
TL;DR: It is shown that Cnp1, which encodes 2′,3′-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly, and the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin.
Journal ArticleDOI
Axonal swellings and degeneration in mice lacking the major proteolipid of myelin
Ian R. Griffiths,Matthias Klugmann,Matthias Klugmann,Matthias Klugmann,Thomas J. Anderson,Thomas J. Anderson,Thomas J. Anderson,Donald Yool,Donald Yool,Donald Yool,Christine E. Thomson,Christine E. Thomson,Christine E. Thomson,Markus H. Schwab,Markus H. Schwab,Markus H. Schwab,Armin Schneider,Armin Schneider,Armin Schneider,Frank Zimmermann,Frank Zimmermann,Frank Zimmermann,Mailise McCulloch,Mailise McCulloch,Mailise McCulloch,Nancy Nadon,Nancy Nadon,Nancy Nadon,Klaus-Armin Nave,Klaus-Armin Nave,Klaus-Armin Nave +30 more
TL;DR: Fiber degeneration could indicate that myelinated axons require local oligodendroglial support, and two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelination.
Journal ArticleDOI
Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis
TL;DR: Evidence is provided that a differentiation block of oligodendroglial progenitors is a major determinant of remyelination failure in chronic multiple sclerosis lesions.