Skip to main content
Log in

Nogo-A Antibodies for Progressive Multiple Sclerosis

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Most of the current therapies, as well as many of the clinical trials, for multiple sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A antibodies administered intravenously or intrathecally. An antibody against a Nogo receptor subunit, leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), was recently shown to improve outcome in patients with acute optic neuritis in a phase II study. Nogo-A-suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate the potential of Nogo-A-antibodies as a therapy for progressive MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. World Health Organization. Multiple Sclerosis International Federation. Atlas: Multiple Sclerosis Resources in the World 2008. Geneva: World Health Organization; 2008. p. 13–7.

    Google Scholar 

  2. Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247–69.

    Article  CAS  PubMed  Google Scholar 

  3. Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tallantyre EC, Bo L, Al-Rawashdeh O, et al. Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease. Brain. 2009;132(Pt 5):1190–9.

    Article  CAS  PubMed  Google Scholar 

  5. Fox RJ, Thompson A, Baker D, et al. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler (Houndmills, Basingstoke, England). 2012;18(11):1534–40.

    Article  Google Scholar 

  6. Torkildsen O, Myhr KM, Bo L. Disease-modifying treatments for multiple sclerosis: a review of approved medications. Eur J Neurol. 2016;23(Suppl. 1):18–27.

    Article  PubMed  Google Scholar 

  7. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.

    Article  PubMed  Google Scholar 

  8. Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Ann Neurol. 2013;74(3):317–27.

    Article  CAS  PubMed  Google Scholar 

  9. Kappos L, Polman C, Pozzilli C, et al. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology. 2001;57(11):1969–75.

    Article  CAS  PubMed  Google Scholar 

  10. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25.

    Article  PubMed  Google Scholar 

  11. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2015;373(15):1418–28.

    Article  CAS  PubMed  Google Scholar 

  12. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9884):2167–75.

    Article  CAS  PubMed  Google Scholar 

  13. Montalban X, Hemmer B, Rammohan K, et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis: results of the phase III double-blind, placebo-controlled ORATORIO study (S49.001). Neurology. 2016;86(16 Suppl.):S49-001.

    Google Scholar 

  14. Hauser S, Comi G, Hartung H-P, et al. Efficacy and safety of ocrelizumab in relapsing multiple sclerosis-results of the interferon-beta-1a-controlled, double-blind, phase III OPERA I and II studies. Mult Scler. 2015;61–2.

  15. McGinley MP, Moss BP, Cohen JA. Safety of monoclonal antibodies for the treatment of multiple sclerosis. Exp Opin Drug Saf. 2017;16(1):89–100.

    Article  CAS  Google Scholar 

  16. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–23.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis: a quiet revolution. Nat Rev Neurol. 2015;11(3):134–42.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2016. doi:10.1007/s00401-016-1631-4.

  19. Shirani A, Okuda DT, Stuve O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics. 2016;13(1):58–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85.

    Article  CAS  PubMed  Google Scholar 

  21. Stadelmann C. Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr Opin Neurol. 2011;24(3):224–9.

    Article  CAS  PubMed  Google Scholar 

  22. Weinshenker BG. The natural history of multiple sclerosis: update 1998. Semin Neurol. 1998;18(3):301–7.

    Article  CAS  PubMed  Google Scholar 

  23. Filippi M, Rocca MA, De Stefano N, et al. Magnetic resonance techniques in multiple sclerosis: the present and the future. Arch Neurol. 2011;68(12):1514–20.

    Article  PubMed  Google Scholar 

  24. Criste G, Trapp B, Dutta R. Axonal loss in multiple sclerosis: causes and mechanisms. Handb Clin Neurol. 2014;122:101–13.

    Article  PubMed  Google Scholar 

  25. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.

    Article  CAS  PubMed  Google Scholar 

  26. Fischer MT, Sharma R, Lim JL, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135(Pt 3):886–99.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Campbell GR, Kraytsberg Y, Krishnan KJ, et al. Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis. Acta Neuropathol. 2012;124(2):209–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Witte ME, Mahad DJ, Lassmann H, van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med. 2014;20(3):179–87.

    Article  PubMed  Google Scholar 

  29. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.

    Article  CAS  PubMed  Google Scholar 

  30. Sorbara CD, Wagner NE, Ladwig A, et al. Pervasive axonal transport deficits in multiple sclerosis models. Neuron. 2014;84(6):1183–90.

    Article  CAS  PubMed  Google Scholar 

  31. Davies AL, Desai RA, Bloomfield PS, et al. Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol. 2013;74(6):815–25.

    Article  CAS  PubMed  Google Scholar 

  32. Desai RA, Davies AL, Tachrount M, et al. Cause and prevention of demyelination in a model multiple sclerosis lesion. Ann Neurol. 2016;79(4):591–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lassmann H. Demyelination and neurodegeneration in multiple sclerosis: the role of hypoxia. Ann Neurol. 2016;79(4):520–1.

    Article  PubMed  Google Scholar 

  34. Patani R, Balaratnam M, Vora A, Reynolds R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol. 2007;33(3):277–87.

    Article  CAS  PubMed  Google Scholar 

  35. Franklin RJ, Gallo V. The translational biology of remyelination: past, present, and future. Glia. 2014;62(11):1905–15.

    Article  PubMed  Google Scholar 

  36. Nave KA. Myelination and support of axonal integrity by glia. Nature. 2010;468(7321):244–52.

    Article  CAS  PubMed  Google Scholar 

  37. Franklin RJ, Ffrench-Constant C, Edgar JM, Smith KJ. Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol. 2012;8(11):624–34.

    Article  PubMed  Google Scholar 

  38. Craner MJ, Newcombe J, Black JA, et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci USA. 2004;101(21):8168–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vergo S, Craner MJ, Etzensperger R, et al. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain. 2011;134(Pt 2):571–84.

    Article  PubMed  Google Scholar 

  40. Friese MA, Craner MJ, Etzensperger R, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007;13(12):1483–9.

    Article  CAS  PubMed  Google Scholar 

  41. Schattling B, Steinbach K, Thies E, et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 2012;18(12):1805–11.

    Article  CAS  PubMed  Google Scholar 

  42. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10(4):225–38.

    Article  CAS  PubMed  Google Scholar 

  43. Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015;78(5):710–21.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mews I, Bergmann M, Bunkowski S, et al. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler. 1998;4(2):55–62.

    Article  CAS  PubMed  Google Scholar 

  45. Bjartmar C, Kidd G, Mork S, et al. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000;48(6):893–901.

    Article  CAS  PubMed  Google Scholar 

  46. Sospedra M, Martin R. Immunology of multiple sclerosis. Ann Rev Immunol. 2005;23:683–747.

    Article  CAS  Google Scholar 

  47. Dubois-Dalcq M, Ffrench-Constant C, Franklin RJ. Enhancing central nervous system remyelination in multiple sclerosis. Neuron. 2005;48(1):9–12.

    Article  CAS  PubMed  Google Scholar 

  48. Wootla B, Denic A, Watzlawik JO, et al. Antibody-mediated oligodendrocyte remyelination promotes axon health in progressive demyelinating disease. Mol Neurobiol. 2016;53(8):5217–28.

    Article  CAS  PubMed  Google Scholar 

  49. Schwab ME. Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci. 2010;11(12):799–811.

    Article  CAS  PubMed  Google Scholar 

  50. Caroni P, Schwab ME. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron. 1988;1(1):85–96.

    Article  CAS  PubMed  Google Scholar 

  51. GrandPre T, Nakamura F, Vartanian T, Strittmatter SM. Identification of the Nogo inhibitor of axon regeneration as a reticulon protein. Nature. 2000;403(6768):439–44.

    Article  CAS  PubMed  Google Scholar 

  52. Chen MS, Huber AB, van der Haar ME, et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature. 2000;403(6768):434–9.

    Article  CAS  PubMed  Google Scholar 

  53. Schwab ME, Strittmatter SM. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol. 2014;27:53–60.

    Article  CAS  PubMed  Google Scholar 

  54. Huber AB, Weinmann O, Brosamle C, et al. Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J Neurosci. 2002;22(9):3553–67.

    CAS  PubMed  Google Scholar 

  55. Dodd DA, Niederoest B, Bloechlinger S, et al. Nogo-A, -B, and -C are found on the cell surface and interact together in many different cell types. J Biol Chem. 2005;280(13):12494–502.

    Article  CAS  PubMed  Google Scholar 

  56. Wang KC, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature. 2002;417(6892):941–4.

    Article  CAS  PubMed  Google Scholar 

  57. Nash M, Pribiag H, Fournier AE, Jacobson C. Central nervous system regeneration inhibitors and their intracellular substrates. Mol Neurobiol. 2009;40(3):224–35.

    Article  CAS  PubMed  Google Scholar 

  58. Kempf A, Tews B, Arzt ME, et al. The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity. PLoS Biol. 2014;12(1):e1001763.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Montani L, Gerrits B, Gehrig P, et al. Neuronal Nogo-A modulates growth cone motility via Rho-GTP/LIMK1/cofilin in the unlesioned adult nervous system. J Biol Chem. 2009;284(16):10793–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gou X, Zhang Q, Xu N, et al. Spatio-temporal expression of paired immunoglobulin-like receptor-B in the adult mouse brain after focal cerebral ischaemia. Brain Inj. 2013;27(11):1311–5.

    Article  PubMed  Google Scholar 

  61. Mi S, Pepinsky RB, Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs. 2013;27(7):493–503.

    Article  CAS  PubMed  Google Scholar 

  62. Barrette B, Vallieres N, Dube M, Lacroix S. Expression profile of receptors for myelin-associated inhibitors of axonal regeneration in the intact and injured mouse central nervous system. Mol Cell Neurosci. 2007;34(4):519–38.

    Article  CAS  PubMed  Google Scholar 

  63. Fujita Y, Yamashita T. Axon growth inhibition by RhoA/ROCK in the central nervous system. Frontiers Neurosci. 2014;8:338.

    Article  Google Scholar 

  64. Teng FY, Tang BL. Why do Nogo/Nogo-66 receptor gene knockouts result in inferior regeneration compared to treatment with neutralizing agents? J Neurochem. 2005;94(4):865–74.

    Article  CAS  PubMed  Google Scholar 

  65. Lee JK, Geoffroy CG, Chan AF, et al. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron. 2010;66(5):663–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schmandke A, Schmandke A, Schwab ME. Nogo-A: multiple roles in CNS development, maintenance, and disease. Neuroscientist. 2014;20(4):372–86.

    Article  CAS  PubMed  Google Scholar 

  67. Chong SY, Rosenberg SS, Fancy SP, et al. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc Natl Acad Sci USA. 2012;109(4):1299–304.

    Article  CAS  PubMed  Google Scholar 

  68. Gonzenbach RR, Zoerner B, Schnell L, et al. Delayed anti-nogo-a antibody application after spinal cord injury shows progressive loss of responsiveness. J Neurotrauma. 2012;29(3):567–78.

    Article  PubMed  Google Scholar 

  69. Wang X, Duffy P, McGee AW, et al. Recovery from chronic spinal cord contusion after Nogo receptor intervention. Ann Neurol. 2011;70(5):805–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tsai SY, Papadopoulos CM, Schwab ME, Kartje GL. Delayed anti-nogo-a therapy improves function after chronic stroke in adult rats. Stroke. 2011;42(1):186–90.

    Article  CAS  PubMed  Google Scholar 

  71. Markus TM, Tsai SY, Bollnow MR, et al. Recovery and brain reorganization after stroke in adult and aged rats. Ann Neurol. 2005;58(6):950–3.

    Article  PubMed  Google Scholar 

  72. Wahl AS, Omlor W, Rubio JC, et al. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science (New York, NY). 2014;344(6189):1250–5.

    Article  CAS  Google Scholar 

  73. Freund P, Schmidlin E, Wannier T, et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat Med. 2006;12(7):790–2.

    Article  CAS  PubMed  Google Scholar 

  74. Zagrebelsky M, Schweigreiter R, Bandtlow CE, et al. Nogo-A stabilizes the architecture of hippocampal neurons. J Neurosci. 2010;30(40):13220–34.

    Article  CAS  PubMed  Google Scholar 

  75. Delekate A, Zagrebelsky M, Kramer S, et al. NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale. Proc Natl Acad Sci. 2011;108(6):2569–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mironova YA, Giger RJ. Where no synapses go: gatekeepers of circuit remodeling and synaptic strength. Trends Neurosci. 2013;36(6):363–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zemmar A, Weinmann O, Kellner Y, et al. Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo. J Neurosci. 2014;34(26):8685–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Wills ZP, Mandel-Brehm C, Mardinly AR, et al. The nogo receptor family restricts synapse number in the developing hippocampus. Neuron. 2012;73(3):466–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee JY, Petratos S. Multiple sclerosis: does Nogo play a role? Neuroscientist. 2013;19(4):394–408.

    Article  PubMed  CAS  Google Scholar 

  80. Karnezis T, Mandemakers W, McQualter JL, et al. The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004;7(7):736–44.

    Article  CAS  PubMed  Google Scholar 

  81. Fontoura P, Ho PP, DeVoss J, et al. Immunity to the extracellular domain of Nogo-A modulates experimental autoimmune encephalomyelitis. J Immunol. 2004;173(11):6981–92.

    Article  CAS  PubMed  Google Scholar 

  82. Fontoura P, Steinman L. Nogo in multiple sclerosis: growing roles of a growth inhibitor. Journal of the neurological sciences. J Neurol Sci. 2006;245(1–2):201–10.

    Article  PubMed  Google Scholar 

  83. Petratos S, Ozturk E, Azari MF, et al. Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain. 2012;135(Pt 6):1794–818.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Yang Y, Liu Y, Wei P, et al. Silencing Nogo-A promotes functional recovery in demyelinating disease. Ann Neurol. 2010;67(4):498–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nikic I, Merkler D, Sorbara C, et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 2011;17(4):495–9.

    Article  CAS  PubMed  Google Scholar 

  86. Tomassini V, d’Ambrosio A, Petsas N, et al. The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence. Hum Brain Mapp. 2016;37(7):2431–45.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bareyre FM, Kerschensteiner M, Raineteau O, et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci. 2004;7(3):269–77.

    Article  CAS  PubMed  Google Scholar 

  88. Kerschensteiner M, Bareyre FM, Buddeberg BS, et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J Exp Med. 2004;200(8):1027–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Theotokis P, Lourbopoulos A, Touloumi O, et al. Time course and spatial profile of Nogo-A expression in experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuropathol Exp Neurol. 2012;71(10):907–20.

    Article  CAS  PubMed  Google Scholar 

  90. Anderson JM, Hampton DW, Patani R, et al. Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain. 2008;131(Pt 7):1736–48.

    Article  CAS  PubMed  Google Scholar 

  91. Denic A, Johnson AJ, Bieber AJ, et al. The relevance of animal models in multiple sclerosis research. Pathophysiology. 2011;18(1):21–9.

    Article  CAS  PubMed  Google Scholar 

  92. Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci. 2005;25(6):1459–69.

    Article  CAS  PubMed  Google Scholar 

  93. Pernet V, Joly S, Christ F, et al. Nogo-A and myelin-associated glycoprotein differently regulate oligodendrocyte maturation and myelin formation. J Neurosci. 2008;28(29):7435–44.

    Article  CAS  PubMed  Google Scholar 

  94. Syed YA, Baer AS, Lubec G, et al. Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins. Neurosurg Focus. 2008;24(3–4):E5.

    Article  PubMed  Google Scholar 

  95. Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005;8(6):745–51.

    Article  CAS  PubMed  Google Scholar 

  96. Mi S, Hu B, Hahm K, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 2007;13(10):1228–33.

    Article  CAS  PubMed  Google Scholar 

  97. Mi S, Miller RH, Tang W, et al. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann Neurol. 2009;65(3):304–15.

    Article  CAS  PubMed  Google Scholar 

  98. Lee X, Yang Z, Shao Z, et al. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. J Neurosci. 2007;27(1):220–5.

    Article  CAS  PubMed  Google Scholar 

  99. Wootla B, Watzlawik JO, Warrington AE, et al. Naturally occurring monoclonal antibodies and their therapeutic potential for neurologic diseases. JAMA Neurol. 2015;72(11):1346–53.

    Article  PubMed  Google Scholar 

  100. Satoh J, Onoue H, Arima K, Yamamura T. Nogo-A and nogo receptor expression in demyelinating lesions of multiple sclerosis. J Neuropathol Exp Neurol. 2005;64(2):129–38.

    Article  CAS  PubMed  Google Scholar 

  101. Reindl M, Khantane S, Ehling R, et al. Serum and cerebrospinal fluid antibodies to Nogo-A in patients with multiple sclerosis and acute neurological disorders. J Neuroimmunol. 2003;145(1–2):139–47.

    Article  CAS  PubMed  Google Scholar 

  102. Meininger V, Pradat PF, Corse A, et al. Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS One. 2014;9(5):e97803.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Tran JQ, Rana J, Barkhof F, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014;1(2):e18.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Cadavid D, Balcer L, Galetta S, et al. Evidence of remyelination with the anti-LINGO-1 monoclonal antibody BIIB033 after acute optic neuritis. Neurology. 2015; E46.

  105. Noseworthy JH, Vandervoort MK, Wong CJ, Ebers GC. Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial: the Canadian Cooperation MS Study Group. Neurology. 1990;40(6):971–5.

    Article  CAS  PubMed  Google Scholar 

  106. di Nuzzo L, Orlando R, Nasca C, Nicoletti F. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis. Drug Design Develop Ther. 2014;8:555–68.

    Google Scholar 

  107. Bonnan M, Ferrari S, Bertandeau E, et al. Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials. Curr Drug Targets. 2014;15(13):1205–14.

    Article  CAS  PubMed  Google Scholar 

  108. Bien-Ly N, Boswell CA, Jeet S, et al. Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies. Neuron. 2015;88(2):289–97.

    Article  CAS  PubMed  Google Scholar 

  109. Pepinsky RB, Shao Z, Ji B, et al. Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration. J Pharmacol Exp Ther. 2011;339(2):519–29.

    Article  CAS  PubMed  Google Scholar 

  110. Petereit HF, Rubbert-Roth A. Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Mult Scler. 2009;15(2):189–92.

    Article  CAS  PubMed  Google Scholar 

  111. Tran J, Palaparthy R, Zhao J, et al. Safety, tolerability and pharmacokinetics of the anti-LINGO-1 monoclonal antibody BIIB033 in healthy volunteers and subjects with multiple sclerosis. Neurology. 2012;78((Meeting Abstracts 1)):P02.021.

    Google Scholar 

  112. Greenberg BM, Rodriguez M, Kantarci O, et al. Safety and tolerability of the remyelinating therapeutic antibody rHIgM22 in patients with stable multiple sclerosis. Neurology. 2015:E48–E49.

  113. Willi R, Schwab ME. Nogo and Nogo receptor: relevance to schizophrenia? Neurobiol Dis. 2013;54:150–7.

    Article  CAS  PubMed  Google Scholar 

  114. Lewis CM, Levinson DF, Wise LH, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet. 2003;73(1):34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Willi R, Weinmann O, Winter C, et al. Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes. J Neurosci. 2010;30(2):556–67.

    Article  CAS  PubMed  Google Scholar 

  116. Budel S, Padukkavidana T, Liu BP, et al. Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J Neurosci. 2008;28(49):13161–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Craveiro LM, Weinmann O, Roschitzki B, et al. Infusion of anti-Nogo-A antibodies in adult rats increases growth and synapse related proteins in the absence of behavioral alterations. Exp Neurol. 2013;250:52–68.

    Article  CAS  PubMed  Google Scholar 

  118. Oertle T, van der Haar ME, Bandtlow CE, et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci. 2003;23(13):5393–406.

    CAS  PubMed  Google Scholar 

  119. Schnell L, Schwab ME. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature. 1990;343(6255):269–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Roman Willi and Miguel Maurer for input and discussion about Nogo-A antibody pharmacology. We are grateful for funding from the Swiss Multiple Sclerosis Society, the Hartmann-Müller Foundation, the Swiss National Science Foundation, the Christopher and Dana Reeve Foundation, and the Desirée-and-Niels-Yde Foundation.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Benjamin V. Ineichen or Martin E. Schwab.

Ethics declarations

Funding

This work was supported by grants of the Swiss National Science Foundation (Grant No. 31003A-149315-1 to MES), the Christopher and Dana Reeve Foundation (to MES), the Swiss Multiple Sclerosis Society, the Hartmann‐Müller Foundation, Zurich, the Desirée‐and‐Niels‐Yde Foundation (to BVI), and an MD‐PhD fellowship of the Swiss National Science Foundation (No. 323530_151488, to BVI). No funding was received specifically for the publication of this article.

Conflict of interest

MES is a founder and board member of the University of Zurich spin-off company NovaGo Therapeutics Inc., seeking to develop Nogo-A antibody-based therapeutics. Benjamin V. Ineichen, Patricia S. Plattner, Nicolas Good, Roland Martin, and Michael Linnebank declare no conflicts of interest.

Additional information

B. V. Ineichen and P. S. Plattner contributed equally and share the first authorship.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ineichen, B.V., Plattner, P.S., Good, N. et al. Nogo-A Antibodies for Progressive Multiple Sclerosis. CNS Drugs 31, 187–198 (2017). https://doi.org/10.1007/s40263-017-0407-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-017-0407-2

Keywords

Navigation