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Fingolimod is a potential novel therapy for multiple sclerosis

Abstract

Fingolimod (also known as FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator that has unique and potent immunoregulatory properties. Mechanistic studies indicate that on phosphorylation fingolimod can bind with high affinity to S1P1 receptors. Persistent modulation of lymphocyte S1P1 receptors by fingolimod and the subsequent internalization of these receptors inhibits lymphocyte egress from the lymph nodes, and prevents these cells from infiltrating inflammatory lesions in the CNS. Results of two phase III studies—FREEDOMS and TRANSFORMS—support previous phase II trial observations indicating that fingolimod exerts powerful anti-inflammatory effects in relapsing–remitting multiple sclerosis (MS). Fingolimod might, therefore, be one of the first orally active drug therapies available for the treatment of relapsing–remitting MS. Moreover, results from preclinical studies suggest that fingolimod might promote neural repair in vivo. In this article, we review the background to these findings, present the proposed immunological and neurobiological profile of fingolimod, discuss the data from the FREEDOMS and TRANSFORMS trials, and provide an expert opinion regarding the future of next-generation S1P receptor modulators for MS therapy.

Key Points

  • Fingolimod is the first member of a novel class of immunomodulatory compounds that targets the lipid mediator sphingosine-1-phosphate signaling system

  • Fingolimod induces pronounced lymphopenia by inhibiting the egress of lymphocytes from secondary lymphoid organs into the circulatory system

  • Fingolimod has direct neuroregenerative effects in vitro

  • Oral fingolimod reduces relapse rates and disease progression in relapsing–remitting multiple sclerosis; head-to-head comparisons suggest that reduction of relapse rate by this drug exceeds the effect of intramuscular interferon β

  • Typical adverse events associated with fingolimod use include lymphopenia, respiratory tract infections and transient bradycardia

  • The causal relationship and possible dose dependency between fingolimod administration and macular edema, skin cancer and reactivation of latent herpes virus infection remains to be established

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Figure 1: The S1P pathway.
Figure 2: S1P receptors in the CNS.
Figure 3: CNS targets of fingolimod.
Figure 4: Proposed neurobiological roles of fingolimod in MS.
Figure 5: Effects of fingolimod in multiple sclerosis.

References

  1. Fujita, T. et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. (Tokyo) 47, 208–215 (1994).

    CAS  Google Scholar 

  2. Brinkmann, V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol. 158, 1173–1182 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schwab, S. R. & Cyster, J. G. Finding a way out: lymphocyte egress from lymphoid organs. Nat. Immunol. 8, 1295–1301 (2007).

    CAS  PubMed  Google Scholar 

  4. Foster, C. A. et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther. 323, 469–475 (2007).

    CAS  PubMed  Google Scholar 

  5. Miron, V. E., Schubart, A. & Antel, J. P. Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci. 274, 13–17 (2008).

    CAS  PubMed  Google Scholar 

  6. Cohen, J. A. et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362, 402–415 (2010).

    CAS  PubMed  Google Scholar 

  7. Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010).

    CAS  PubMed  Google Scholar 

  8. Takabe, K., Paugh, S. W., Milstien, S. & Spiegel, S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60, 181–195 (2008).

    CAS  PubMed  Google Scholar 

  9. Fukushima, N., Ishii, I., Contos, J. J., Weiner, J. A. & Chun, J. Lysophospholipid receptors. Annu. Rev. Pharmacol. Toxicol. 41, 507–534 (2001).

    CAS  PubMed  Google Scholar 

  10. Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell Biol. 4, 397–407 (2003).

    CAS  PubMed  Google Scholar 

  11. Gardell, S. E., Dubin, A. E. & Chun, J. Emerging medicinal roles for lysophospholipid signaling. Trends Mol. Med. 12, 65–75 (2006).

    CAS  PubMed  Google Scholar 

  12. Chun, J. et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 54, 265–269 (2002).

    CAS  PubMed  Google Scholar 

  13. Dev, K. K. et al. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther. 117, 77–93 (2008).

    CAS  PubMed  Google Scholar 

  14. Budde, K. et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J. Am. Soc. Nephrol. 13, 1073–1083 (2002).

    CAS  PubMed  Google Scholar 

  15. Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol. 160, 5037–5044 (1998).

    CAS  PubMed  Google Scholar 

  16. Henning, G. et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J. Exp. Med. 194, 1875–1881 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).

    CAS  PubMed  Google Scholar 

  18. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

    CAS  PubMed  Google Scholar 

  19. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    CAS  PubMed  Google Scholar 

  20. Mullershausen, F. et al. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat. Chem. Biol. 5, 428–434 (2009).

    CAS  PubMed  Google Scholar 

  21. Rivera, J., Proia, R. L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat. Rev. Immunol. 8, 753–763 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Walzer, T. et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat. Immunol. 8, 1337–1344 (2007).

    CAS  PubMed  Google Scholar 

  23. Michaud, J., Im, D. S. & Hla, T. Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation. J. Immunol. 184, 1475–1483 (2010).

    CAS  PubMed  Google Scholar 

  24. Pederson, L., Ruan, M., Westendorf, J. J., Khosla, S. & Oursler, M. J. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc. Natl Acad. Sci. USA 105, 20764–20769 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ishii, M. et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458, 524–528 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nat. Immunol. 5, 713–720 (2004).

    CAS  PubMed  Google Scholar 

  27. Cinamon, G., Zachariah, M. A., Lam, O. M., Foss, F. W. Jr & Cyster, J. G. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat. Immunol. 9, 54–62 (2008).

    CAS  PubMed  Google Scholar 

  28. Donovan, E. E., Pelanda, R. & Torres, R. M. S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development. Eur. J. Immunol. 40, 688–698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393–407 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Venken, K., Hellings, N., Liblau, R. & Stinissen, P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol. Med. 16, 58–68 (2010).

    CAS  PubMed  Google Scholar 

  31. Gandhi, R., Laroni, A. & Weiner, H. L. Role of the innate immune system in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 221, 7–14 (2009).

    Google Scholar 

  32. Lunemann, J. D. & Munz, C. Do natural killer cells accelerate or prevent autoimmunity in multiple sclerosis? Brain 131, 1681–1683 (2008).

    PubMed  Google Scholar 

  33. Frohman, E. M., Racke, M. K. & Raine, C. S. Multiple sclerosis—the plaque and its pathogenesis. N. Engl. J. Med. 354, 942–955 (2006).

    CAS  PubMed  Google Scholar 

  34. Beer, M. S. et al. EDG receptors as a therapeutic target in the nervous system. Ann. NY Acad. Sci. 905, 118–131 (2000).

    CAS  PubMed  Google Scholar 

  35. Teshima, K. et al. FTY720, a novel immunosuppressant, possessing unique mechanisms III. Pharmacological activities in several autoimmune and inflammatory models [abstract 864]. In Abstracts of the 9th International Congress of Immunology. 5126 (1995).

    Google Scholar 

  36. Steinman, L. & Zamvil, S. S. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol. 26, 565–571 (2005).

    CAS  PubMed  Google Scholar 

  37. Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).

    PubMed  Google Scholar 

  38. Stromnes, I. M. & Goverman, J. M. Active induction of experimental allergic encephalomyelitis. Nat. Protoc. 1, 1810–1819 (2006).

    CAS  PubMed  Google Scholar 

  39. Ben-Nun, A., Wekerle, H. & Cohen, I. R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur. J. Immunol. 11, 195–199 (1981).

    CAS  PubMed  Google Scholar 

  40. Aktas, O., Ullrich, O., Infante-Duarte, C., Nitsch, R. & Zipp, F. Neuronal damage in brain inflammation. Arch. Neurol. 64, 185–189 (2007).

    PubMed  Google Scholar 

  41. Ransohoff, R. M. EAE: pitfalls outweigh virtues of screening potential treatments for multiple sclerosis. Trends Immunol. 27, 167–168 (2006).

    CAS  PubMed  Google Scholar 

  42. Bartholomaus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

    PubMed  Google Scholar 

  43. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).

    CAS  PubMed  Google Scholar 

  44. Aktas, O. et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46, 421–432 (2005).

    CAS  PubMed  Google Scholar 

  45. Krishnamoorthy, G. et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat. Med. 15, 626–632 (2009).

    CAS  PubMed  Google Scholar 

  46. Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305, 70–77 (2003).

    CAS  PubMed  Google Scholar 

  47. Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat. Immunol. 10, 769–777 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Webb, M. et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing–remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol. 153, 108–121 (2004).

    CAS  PubMed  Google Scholar 

  49. Kataoka, H. et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol. Immunol. 2, 439–448 (2005).

    CAS  PubMed  Google Scholar 

  50. Rausch, M. et al. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultra small superparamagnetic iron oxide-enhanced magnetic resonance imaging. J. Magn. Reson. Imaging 20, 16–24 (2004).

    PubMed  Google Scholar 

  51. Balatoni, B. et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res. Bull. 74, 307–316 (2007).

    CAS  PubMed  Google Scholar 

  52. Papadopoulos, D. et al. FTY720 ameliorates MOG-induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses. J. Neurosci. Res. 88, 346–359 (2009).

    Google Scholar 

  53. Foster, C. A. et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood–brain-barrier damage. Brain Pathol. 19, 254–266 (2009).

    CAS  PubMed  Google Scholar 

  54. Brinkmann, V., Cyster, J. G. & Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. 4, 1019–1025 (2004).

    CAS  PubMed  Google Scholar 

  55. Lee, J. F. et al. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J. Biol. Chem. 281, 29190–29200 (2006).

    CAS  PubMed  Google Scholar 

  56. Miron, V. E. et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol. 63, 61–71 (2008).

    CAS  PubMed  Google Scholar 

  57. Miron, V. E., Hall, J. A., Kennedy, T. E., Soliven, B. & Antel, J. P. Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. Am. J. Pathol. 173, 1143–1152 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Coelho, R. P., Payne, S. G., Bittman, R., Spiegel, S. & Sato-Bigbee, C. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J. Pharmacol. Exp. Ther. 323, 626–635 (2007).

    CAS  PubMed  Google Scholar 

  59. Jung, C. G. et al. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 55, 1656–1667 (2007).

    CAS  PubMed  Google Scholar 

  60. Novgorodov, A. S., El-Alwani, M., Bielawski, J., Obeid, L. M. & Gudz, T. I. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J. 21, 1503–1514 (2007).

    CAS  PubMed  Google Scholar 

  61. Miron, V. E. et al. The immunomodulator fingolimod (FTY720) increases myelin production following demyelination of organotypic cerebellar slices [abstract S47.003]. Neurology 72 (Suppl. 3), A421 (2009).

    Google Scholar 

  62. Rouach, N. et al. S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK. Eur. J. Neurosci. 23, 1453–1464 (2006).

    PubMed  Google Scholar 

  63. Osinde, M., Mullershausen, F. & Dev, K. K. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 52, 1210–1218 (2007).

    CAS  PubMed  Google Scholar 

  64. Sofroniew, M. V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Prozorovski, T. et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat. Cell Biol. 10, 385–394 (2008).

    CAS  PubMed  Google Scholar 

  66. Kremer, D. et al. p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation. Proc. Natl Acad. Sci. USA 106, 9087–9092 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mullershausen, F. et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J. Neurochem. 102, 1151–1161 (2007).

    CAS  PubMed  Google Scholar 

  68. Pebay, A. et al. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur. J. Neurosci. 13, 2067–2076 (2001).

    PubMed  Google Scholar 

  69. Postma, F. R., Jalink, K., Hengeveld, T. & Moolenaar, W. H. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J. 15, 2388–2392 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Edsall, L. C., Pirianov, G. G. & Spiegel, S. Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J. Neurosci. 17, 6952–6960 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Moore, A. N., Kampfl, A. W., Zhao, X., Hayes, R. L. & Dash, P. K. Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes. Neuroscience 94, 405–415 (1999).

    CAS  PubMed  Google Scholar 

  72. Toman, R. E. et al. Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J. Cell Biol. 166, 381–392 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Harada, J., Foley, M., Moskowitz, M. A. & Waeber, C. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J. Neurochem. 88, 1026–1039 (2004).

    CAS  PubMed  Google Scholar 

  74. Kimura, A. et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells 25, 115–124 (2007).

    CAS  PubMed  Google Scholar 

  75. Picard-Riera, N. et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci. USA 99, 13211–13216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Mizugishi, K. et al. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell Biol. 25, 11113–11121 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kappos, L. et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 355, 1124–1140 (2006).

    CAS  PubMed  Google Scholar 

  79. Mehling, M. et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71, 1261–1267 (2008).

    CAS  PubMed  Google Scholar 

  80. O'Connor, P. et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 72, 73–79 (2009).

    CAS  PubMed  Google Scholar 

  81. Hartung, H. P. & Aktas, O. Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann. Neurol. 66, 429–432 (2009).

    CAS  PubMed  Google Scholar 

  82. Saab, G., Almony, A., Blinder, K. J., Schuessler, R. & Brennan, D. C. Reversible cystoid macular edema secondary to fingolimod in a renal transplant recipient. Arch. Ophthalmol. 126, 140–141 (2008).

    PubMed  Google Scholar 

  83. Hartung, H. P. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol. 8, 28–31 (2009).

    PubMed  Google Scholar 

  84. Leypoldt, F. et al. Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report. Neurology 72, 1022–1024 (2009).

    CAS  PubMed  Google Scholar 

  85. Hartung, H. P. & Aktas, O. Oral therapies for multiple sclerosis: are we there yet? Lancet Neurol. 9, 454–457 (2010).

    PubMed  Google Scholar 

  86. Kovarik, J. M. et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J. Clin. Pharmacol. 46, 149–156 (2006).

    CAS  PubMed  Google Scholar 

  87. Schmouder, R. et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J. Clin. Pharmacol. 46, 895–904 (2006).

    CAS  PubMed  Google Scholar 

  88. Sanna, M. G. et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839–13848 (2004).

    CAS  PubMed  Google Scholar 

  89. Gergely, P. et al. Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans [Poster P437]. In Abstracts of the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Düsseldorf (2009).

    Google Scholar 

  90. Aktas, O., Kieseier, B. & Hartung, H. P. Neuroprotection, regeneration and immunomodulation: broadening the therapeutic repertoire in multiple sclerosis. Trends Neurosci. 33, 140–152 (2010).

    CAS  PubMed  Google Scholar 

  91. Schulze-Topphoff, U. et al. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nat. Med. 15, 788–793 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Schwab, S. R. et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735–1739 (2005).

    CAS  PubMed  Google Scholar 

  93. Bagdanoff, J. T. et al. Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders. J. Med. Chem. 52, 3941–3953 (2009).

    CAS  PubMed  Google Scholar 

  94. Hartung, H. P., Aktas, O., Kieseier, B. & Comi, G. Development of oral cladribine for the treatment of multiple sclerosis. J. Neurol. 257, 163–170 (2009).

    Google Scholar 

  95. Ishii, I., Fukushima, N., Ye, X. & Chun, J. Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73, 321–354 (2004).

    CAS  PubMed  Google Scholar 

  96. Kobashi, H. et al. Lysophospholipid receptors are differentially expressed in rat terminal Schwann cells, as revealed by a single cell rt-PCR and in situ hybridization. Acta Histochem. Cytochem. 39, 55–60 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther. 115, 84–105 (2007).

    CAS  PubMed  Google Scholar 

  98. Bandhuvula, P., Tam, Y. Y., Oskouian, B. & Saba, J. D. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J. Biol. Chem. 280, 33697–33700 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Chun (Department of Molecular Biology, H. L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA, USA) for critical reading of the manuscript and valuable suggestions. We thank J. Ingwersen (Department of Neurology, Heinrich-Heine-University of Düsseldorf, Germany) for help in creating Supplementary Table 2.

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Correspondence to Hans-Peter Hartung.

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Competing interests

O. Aktas has received honoraria from Bayer HealthCare, Merck Serono, Novartis and Talecris for lectures. B. Kieseier has received honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, Talecris and Teva for lectures and honoraria from Biogen Idec, Novartis, Sanofi Aventis and Teva for consulting. He has also received research funding from Bayer HealthCare, Biogen Idec, Merck Serono and Teva. H. P. Hartung has received honoraria from Bayer HealthCare, Biogen Idec, BioMS Genzyme, Merck Serono, Novartis, Sanofi Aventis and Teva for lectures. He has also received research funding from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva. P. Küry declares no competing interests.

Supplementary information

Supplementary Table 1

Preclinical studies investigating the impact of fingolimod in experimental autoimmune encephalomyelitis (DOC 59 kb)

Supplementary Table 2

Occurrence and frequency of adverse events reported in fingolimod phase III trials (FREEDOMS & TRANSFORMS) (DOC 73 kb)

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Aktas, O., Küry, P., Kieseier, B. et al. Fingolimod is a potential novel therapy for multiple sclerosis. Nat Rev Neurol 6, 373–382 (2010). https://doi.org/10.1038/nrneurol.2010.76

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