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  • Review Article
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Emerging therapies to target CNS pathophysiology in multiple sclerosis

Nature Reviews Neurology volume 18, pages 466–475 (2022)Cite this article

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Abstract

The rapidly evolving therapeutic landscape of multiple sclerosis (MS) has contributed to paradigm shifts in our understanding of the biological mechanisms that contribute to CNS injury and in treatment philosophies. Opportunities remain to further improve treatment of relapsing–remitting MS, but two major therapeutic gaps are the limiting of progressive disease mechanisms and the repair of CNS injury. In this Review, we provide an overview of selected emerging therapies that predominantly target processes within the CNS that are thought to be involved in limiting non-relapsing, progressive disease injury or promoting tissue repair. Among these, we consider agents that modulate adaptive and innate CNS-compartmentalized inflammation, which can be mediated by infiltrating immune cells and/or resident CNS cells, including microglia and astrocytes. We also discuss agents that target degenerative disease mechanisms, agents that might confer neuroprotection, and agents that create a more favourable environment for or actively contribute to oligodendrocyte precursor cell differentiation, remyelination and axonal regeneration. We focus on agents that are novel for MS, that are known to or are presumed to penetrate the CNS, and that have already entered early stages of development in MS clinical trials.

Key points

  • Therapeutic agents that limit progressive disease mechanisms and repair CNS injury are an important unmet need in multiple sclerosis (MS) clinical practice.

  • A number of emerging therapies target compartmentalized inflammation, remyelination and neuroprotection, and could be beneficial in progressive MS and CNS repair.

  • Emerging therapies that target CNS inflammation include Bruton tyrosine kinase inhibitors, CD40 ligand antibodies and α-lipoic acid.

  • Emerging therapies that provide neuroprotection include masitinib, ibudilast, metformin, clomipramine and receptor-interacting protein kinase 1.

  • Emerging therapies that disinhibit CNS repair include elezanumab and opicinumab, and those that promote CNS repair include proteoglycans, niacin, muscarinic receptor antagonists and temelimab.

  • Many candidate drugs require validation in large clinical trials, but their emergence opens the door to new treatment algorithms and personalized therapy in MS.

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References

  1. Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391, 1622–1636 (2018).

    Article  PubMed  Google Scholar 

  2. Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169–180 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bar-Or, A. & Li, R. Cellular immunology of relapsing multiple sclerosis: interactions, checks, and balances. Lancet Neurol. 20, 470–483 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mahad, D. H., Trapp, B. D. & Lassmann, H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183–193 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Fadda, G. et al. A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis. Ann. Neurol. 85, 340–351 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pardini, M., Brown, J. W. L., Magliozzi, R., Reynolds, R. & Chard, D. T. Surface-in pathology in multiple sclerosis: a new view on pathogenesis? Brain 144, 1646–1654 (2021).

    Article  PubMed  Google Scholar 

  8. Dal-Bianco, A. et al. Long-term evolution of multiple sclerosis iron rim lesions in 7T MRI. Brain 144, 833–847 (2021).

    Article  PubMed  Google Scholar 

  9. Maggi, P. et al. Paramagnetic rim lesions are specific to multiple sclerosis: an international multicenter 3T MRI study. Ann. Neurol. 88, 1034–1042 (2020).

    Article  PubMed  Google Scholar 

  10. Absinta, M. et al. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 597, 709–714 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lisak, R. P. et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J. Neuroimmunol. 246, 85–95 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).

    Article  PubMed  Google Scholar 

  13. Haider, L. et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain 139, 807–815 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hauser, S. L. & Cree, B. A. C. Treatment of multiple sclerosis: a review. Am. J. Med. 133, 1380–1390.e2 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Freedman, M. S. et al. Treatment optimization in multiple sclerosis: Canadian MS working group recommendations. Can. J. Neurol. Sci. 47, 437–455 (2020).

    Article  PubMed  Google Scholar 

  16. Montalban, X. et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult. Scler. 24, 96–120 (2018).

    Article  PubMed  Google Scholar 

  17. Hartkamp, L. M. et al. Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants. Ann. Rheum. Dis. 74, 1603–1611 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Corneth, O. B. J. et al. Enhanced Bruton’s tyrosine kinase activity in peripheral blood B lymphocytes from patients with autoimmune disease. Arthritis Rheumatol. 69, 1313–1324 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Mano, H. The Tec family protein-tyrosine kinases: a subset of kinases for a subset of signalings. Int. J. Hematol. 69, 6–12 (1999).

    CAS  PubMed  Google Scholar 

  20. Carnero Contentti, E. & Correale, J. Bruton’s tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis. Expert. Opin. Emerg. Drugs 25, 377–381 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Machado-Santos, J. et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141, 2066–2082 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Torke, S. et al. Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol. 140, 535–548 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, R. et al. BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy. Acta Neuropathol. 143, 505–521 (2022). This study delineated important mechanisms underlying the therapeutic potential of BTK inhibitors in MS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Owens, T. D. et al. Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). Clin. Transl. Sci. 15, 442–450 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Mangla, A. et al. Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses. Blood 104, 1191–1197 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Hata, D. et al. Involvement of Bruton’s tyrosine kinase in FcεRI-dependent mast cell degranulation and cytokine production. J. Exp. Med. 187, 1235–1247 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Montalban, X. et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N. Engl. J. Med. 380, 2406–2417 (2019). This was the first phase II clinical trial that demonstrated the efficacy of a BTK inhibitor (evobrutinib) on MRI measures of interest in relapsing–remitting MS.

    Article  CAS  PubMed  Google Scholar 

  28. Smith P. F., et al. Phase 1 clinical trial of PRN2246 (SAR441268), a covalent BTK inhibitor demonstrates safety, CNS exposure and therapeutic levels of BTK occupancy. Mult. Scler. 25, 157–165 (2019).

    Google Scholar 

  29. Reich, D. S. et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 20, 729–738 (2021). This phase II clinical trial demonstrated the efficacy of tolebrutinib on MRI measures of interest in relapsing–remitting MS using a unique clinical trial design.

    Article  CAS  PubMed  Google Scholar 

  30. Cohen, S. et al. Fenebrutinib versus placebo or adalimumab in rheumatoid arthritis: a randomized, double-blind, phase II trial (ANDES study). Arthritis Rheumatol. https://doi.org/10.1002/art.41275 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Peters, A. L., Stunz, L. L. & Bishop, G. A. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. D’Aversa, T. G., Weidenheim, K. M. & Berman, J. W. CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. Am. J. Pathol. 160, 559–567 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  33. de Goer de Herve, M. G., Delfraissy, J. F. & Taoufik, Y. Following direct CD40 activation, human primary microglial cells produce IL-12 p40 but not bioactive IL-12 p70. Cytokine 14, 88–96 (2001).

    Article  PubMed  CAS  Google Scholar 

  34. Girvin, A. M., Dal Canto, M. C. & Miller, S. D. CD40/CD40L interaction is essential for the induction of EAE in the absence of CD28-mediated co-stimulation. J. Autoimmun. 18, 83–94 (2002).

    Article  PubMed  Google Scholar 

  35. Aarts, S. A. et al. Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis. J. Pathol. 247, 471–480 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Du, L., Chang, H., Wei, Y., Zhang, X. & Yin, L. Different roles of soluble CD40 ligand in central nervous system damage. Neurol. Res. 42, 372–378 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Davidson, D. C. et al. Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders. PLoS ONE 7, e51793 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Masuda, H. et al. Soluble CD40 ligand contributes to blood-brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder. J. Neuroimmunol. 305, 102–107 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Couzin, J. Drug discovery. Magnificent obsession. Science 307, 1712–1715 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Sidiropoulos, P. I. & Boumpas, D. T. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391–397 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Vaitaitis, G. M., Yussman, M. G. & Wagner, D. H. Jr. A CD40 targeting peptide prevents severe symptoms in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 332, 8–15 (2019). This study demonstrated the potential therapeutic benefit of targeting CD40 ligand in EAE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chamberlain, C. et al. Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles. Ann. Rheum. Dis. 76, 1837–1844 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Furie, R. A. et al. Phase 2, randomized, placebo-controlled trial of dapirolizumab pegol in patients with moderate-to-severe active systemic lupus erythematosus. Rheumatology 60, 5397–5407 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Morini, M. et al. α-Lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 148, 146–153 (2004). This study demonstrated the potential therapeutic benefit of α-lipoic acid in EAE.

    Article  CAS  PubMed  Google Scholar 

  45. Marracci, G. H., Jones, R. E., McKeon, G. P. & Bourdette, D. N. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J. Neuroimmunol. 131, 104–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Chaudhary, P. et al. Effects of lipoic acid on primary murine microglial cells. J. Neuroimmunol. 334, 576972 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yadav, V. et al. Lipoic acid in multiple sclerosis: a pilot study. Mult. Scler. 11, 159–165 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Khalili, M. et al. Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation 21, 291–296 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Spain, R. et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol. Neuroimmunol. Neuroinflamm. 4, e374 (2017). This phase II clinical trial demonstrated the efficacy of lipoic acid in reducing annual brain atrophy in secondary progressive MS.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Falardeau, J. et al. Oral lipoic acid as a treatment for acute optic neuritis: a blinded, placebo controlled randomized trial. Mult. Scler. J. Exp. Transl. Clin. 5, 2055217319850193 (2019).

    PubMed  PubMed Central  Google Scholar 

  51. Elieh-Ali-Komi, D. & Cao, Y. Role of mast cells in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. Clin. Rev. Allergy Immunol. 52, 436–445 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Conti, P. & Kempuraj, D. Important role of mast cells in multiple sclerosis. Mult. Scler. Relat. Disord. 5, 77–80 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Dubreuil, P. et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS ONE 4, e7258 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Christy, A. L. & Brown, M. A. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J. Immunol. 179, 2673–2679 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Bebo, B. F. Jr., Yong, T., Orr, E. L. & Linthicum, D. S. Hypothesis: a possible role for mast cells and their inflammatory mediators in the pathogenesis of autoimmune encephalomyelitis. J. Neurosci. Res. 45, 340–348 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Sayed, B. A., Christy, A. L., Walker, M. E. & Brown, M. A. Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment? J. Immunol. 184, 6891–6900 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Pinke, K. H., Zorzella-Pezavento, S. F. G., Lara, V. S. & Sartori, A. Should mast cells be considered therapeutic targets in multiple sclerosis. Neural Regen. Res. 15, 1995–2007 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Skaper, S. D., Facci, L., Romanello, S. & Leon, A. Mast cell activation causes delayed neurodegeneration in mixed hippocampal cultures via the nitric oxide pathway. J. Neurochem. 66, 1157–1166 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Bidri, M. et al. Mast cells as a source and target for nitric oxide. Int. Immunopharmacol. 1, 1543–1558 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Vermersch, P. et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 12, 36 (2012). This pilot study demonstrated possible clinical efficacy of masitinib in primary progressive MS, prompting further clinical trials.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vermersch, P. et al. Efficacy and safety of masitinib in progressive forms of multiple sclerosis: a randomized, phase 3, clinical trial. Neurol. Neuroimmunol. Neuroinflamm. https://doi.org/10.1212/NXI.0000000000001148 (2022). This phase II clinical trial demonstrated the efficacy of masitinib in reducing disability progression in people with primary progressve MS and non-active secondary progressive MS.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Fox, R. J. et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N. Engl. J. Med. 379, 846–855 (2018). This phase II clinical trial demonstrated the efficacy of ibudilast in reducing the rate of brain atrophy in people with progressive MS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ruiz-Perez, D. et al. The effects of the toll-like receptor 4 antagonist, ibudilast, on sevoflurane’s minimum alveolar concentration and the delayed remifentanil-induced increase in the minimum alveolar concentration in rats. Anesth. Analg. 122, 1370–1376 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Miranda-Hernandez, S. & Baxter, A. G. Role of toll-like receptors in multiple sclerosis. Am. J. Clin. Exp. Immunol. 2, 75–93 (2013).

    PubMed  PubMed Central  Google Scholar 

  65. Suzumura, A., Ito, A., Yoshikawa, M. & Sawada, M. Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res. 837, 203–212 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Gibson, L. C. et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur. J. Pharmacol. 538, 39–42 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Knott, E. P., Assi, M., Rao, S. N., Ghosh, M. & Pearse, D. D. Phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18040696 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Cho, Y. et al. Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc. Natl Acad. Sci. USA 107, 11313–11318 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Naismith, R. T. et al. Effects of ibudilast on MRI measures in the phase 2 SPRINT-MS study. Neurology 96, e491–e500 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Barkhof, F. et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology 74, 1033–1040 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Sormani, M. P., Tur, C. & Barkhof, F. Ibudilast: a paradigm shift for progressive multiple sclerosis? Neurology 96, 141–142 (2021).

    Article  PubMed  Google Scholar 

  72. Nath, N. et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J. Immunol. 182, 8005–8014 (2009). This study demonstrated the potential therapeutic benefit of metformin in preclincal models of MS.

    Article  CAS  PubMed  Google Scholar 

  73. Cunniffe, N. et al. Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis. J. Neurol. Neurosurg. Psychiatry https://doi.org/10.1136/jnnp-2020-324286 (2020). This study systematically evaluated existing drugs that have the potential to be repurposed as treatments for progressive MS and identified a short list of potential candidates.

    Article  PubMed  Google Scholar 

  74. Meng, X. et al. Metformin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury by down-regulating MAD2B. Cell Physiol. Biochem. 40, 477–485 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Neumann, B. et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell 25, 473–485.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Negrotto, L., Farez, M. F. & Correale, J. Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. JAMA Neurol. 73, 520–528 (2016). This pilot study demonstrated the potential benefit of metformin and pioglitazone on MRI and biological measures of MS disease activity.

    Article  PubMed  Google Scholar 

  77. Faissner, S. et al. Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nat. Commun. 8, 1990 (2017). This study systematically evaluated existing drugs that have the potential to be repurposed as treatments for progressive MS and identified a short list of potential candidates, including clomipramine.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Comi, G. et al. Role of B cells in multiple sclerosis and related disorders. Ann. Neurol. 89, 13–23 (2021).

    Article  PubMed  Google Scholar 

  79. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Wallach, D., Kang, T. B., Dillon, C. P. & Green, D. R. Programmed necrosis in inflammation: toward identification of the effector molecules. Science 352, aaf2154 (2016).

    Article  PubMed  CAS  Google Scholar 

  81. Zheng, T. S. & Flavell, R. A. Divinations and surprises: genetic analysis of caspase function in mice. Exp. Cell Res. 256, 67–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Shutinoski, B. et al. K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo. Cell Death Differ. 23, 1628–1637 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yuan, J., Amin, P. & Ofengeim, D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat. Rev. Neurosci. 20, 19–33 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836–1849 (2015). This study provided important insights into the role of necroptosis and relevant molecules in MS pathophysiology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhu, K. et al. Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression. Cell Death Dis. 9, 500 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kim, S. J. & Li, J. Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia. Cell Death Dis. 4, e716 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yoshikawa, M. et al. Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as potent, orally available, and brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships. J. Med. Chem. q, 2384–2409 (2018).

    Article  CAS  Google Scholar 

  88. Chen, Y. et al. Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 371, 229–241 (2018).

    Article  CAS  PubMed  Google Scholar 

  89. & Weisel, K. et al. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers. Pharmacol. Res. Perspect. 5, e00365 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  90. Grievink, H. W. et al. DNL104, a centrally penetrant RIPK1 inhibitor, inhibits RIP1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers. Clin. Pharmacol. Ther. 107, 406–414 (2020). This phase I clinical trial evaluated a centrally penetrant RIPK1 inhibitor at multiple doses in healthy volunteers.

    Article  CAS  PubMed  Google Scholar 

  91. Muramatsu, R. et al. RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. Nat. Med. 17, 488–494 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Demicheva, E. et al. Targeting repulsive guidance molecule A to promote regeneration and neuroprotection in multiple sclerosis. Cell Rep. 10, 1887–1898 (2015). This study demonstrated the therapeutic regenerative potential of RGMa antibodies in preclinical models of MS.

    Article  CAS  PubMed  Google Scholar 

  93. Hata, K. et al. RGMa inhibition promotes axonal growth and recovery after spinal cord injury. J. Cell Biol. 173, 47–58 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tanabe, S., Fujita, Y., Ikuma, K. & Yamashita, T. Inhibiting repulsive guidance molecule-a suppresses secondary progression in mouse models of multiple sclerosis. Cell Death Dis. 9, 1061 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ziemann, A., Rosebraugh, M., Barger, B. & Cree, B. A phase 1, multiple-dose study of elezanumab (ABT-555) in patients with relapsing forms of multiple sclerosis [abstract]. Neurology 92 (Suppl. 15), S56.001 (2019). This phase I trial evaluated RGMa antibodies in people with MS.

    Google Scholar 

  96. Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci. 8, 745–751 (2005). This study demonstrated in vitro and in animal models the role that LINGO1 plays in preventing remyelination by oligodendrocytes.

    Article  CAS  PubMed  Google Scholar 

  97. Mi, S., Pepinsky, R. B. & Cadavid, D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs 27, 493–503 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Mi, S. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med. 13, 1228–1233 (2007). This study demonstrated the therapeutic remyelinating potential of LINGO1 antagonism in EAE.

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, Y. et al. Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination. Exp. Neurol. 266, 68–73 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Ranger, A. et al. Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies. Neurol. Neuroimmunol. Neuroinflamm. 5, e417 (2018).

    Article  PubMed  Google Scholar 

  101. Tran, J. Q. et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol. Neuroimmunol. Neuroinflamm 1, e18 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Cadavid, D. et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 16, 189–199 (2017). This was the first phase II clinical trial to evaluate opicinumab in people with MS and acute optic neuritis.

    Article  CAS  PubMed  Google Scholar 

  103. Cadavid, D. et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 18, 845–856 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Zhu, B. et al. Phase 2 AFFINITY trial evaluates opicinumab in a targeted population of patients with relapsing multiple sclerosis: rationale, design and baseline characteristics [abstract]. Neurology 92 (Suppl. 15), P3.2-072 (2019).

    Google Scholar 

  105. Figueiredo, M. Biogen discontinues development of opicinumab for MS. Multiple Sclerosis News Today https://multiplesclerosisnewstoday.com/news-posts/2020/10/26/biogen-discontinues-development-opicinumab-data-affinity-trial/ (2020).

  106. Huntemann, N. et al. Failed, interrupted, or inconclusive trials on neuroprotective and neuroregenerative treatment strategies in multiple sclerosis: update 2015–2020. Drugs 81, 1031–1063 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Keough, M. B. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat. Commun. 7, 11312 (2016). This study demonstrated the role of CSPGs in preventing remyelination and the therapeutic remyelinating potential of a novel CSPG inhibitor in vitro and in preclinical models of demyelination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Asher, R. A. et al. Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J. Neurosci. 20, 2427–2438 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Beggah, A. T. et al. Lesion-induced differential expression and cell association of neurocan, brevican, versican V1 and V2 in the mouse dorsal root entry zone. Neuroscience 133, 749–762 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Pu, A., Stephenson, E. L. & Yong, V. W. The extracellular matrix: focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies. Glia 66, 1809–1825 (2018).

    Article  PubMed  Google Scholar 

  111. Galtrey, C. M. & Fawcett, J. W. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res. Rev. 54, 1–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Lau, L. W. et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann. Neurol. 72, 419–432 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Stephenson, E. L. et al. Chondroitin sulfate proteoglycans as novel drivers of leucocyte infiltration in multiple sclerosis. Brain 141, 1094–1110 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Pu, A. et al. The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination. J. Neuroinflamm. 17, 220 (2020).

    Article  CAS  Google Scholar 

  115. Stephenson, E. L. et al. Targeting the chondroitin sulfate proteoglycans: evaluating fluorinated glucosamines and xylosides in screens pertinent to multiple sclerosis. ACS Cent. Sci. 5, 1223–1234 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kumar, N. Nutrients and neurology. Continuum 23, 822–861 (2017).

    PubMed  Google Scholar 

  117. Zhang, J. et al. Niaspan treatment improves neurological functional recovery in experimental autoimmune encephalomyelitis mice. Neurobiol. Dis. 32, 273–280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kaneko, S. et al. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J. Neurosci. 26, 9794–9804 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Rawji, K. S. et al. Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system. Acta Neuropathol. 139, 893–909 (2020). This study demonstrated the therapeutic remyelinating potential of niacin in vitro and in preclinical models of demyelination.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Metz, L. M. & Eliasziw, M. Trial of minocycline in clinically isolated syndrome of multiple sclerosis. N. Engl. J. Med. 377, 788–789 (2017).

    Article  Google Scholar 

  121. Mei, F. et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 20, 954–960 (2014). This study demonstrated the utility of a high-throughput screening platform to identify drugs with remyelinating potential, including anti-muscarinic agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Deshmukh, V. A. et al. A regenerative approach to the treatment of multiple sclerosis. Nature 502, 327–332 (2013). This study used an image-based screen to identify drugs with regenerative potential and demonstrated the therapeutic remyelinating potential of benztropine in preclinical models of MS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Green, A. J. et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 390, 2481–2489 (2017). This phase II clinical trial demonstrated the efficacy of clemastine fumarate in chronic demyelinating optic neuropathy.

    Article  CAS  PubMed  Google Scholar 

  124. Morandi, E. et al. The association between human endogenous retroviruses and multiple sclerosis: a systematic review and meta-analysis. PLoS ONE 12, e0172415 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Levet, S. et al. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. JCI Insight https://doi.org/10.1172/jci.insight.94387 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Perron, H. & Lang, A. The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clin. Rev. Allergy Immunol. 39, 51–61 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Faucard, R. et al. Human endogenous retrovirus and neuroinflammation in chronic inflammatory demyelinating polyradiculoneuropathy. EBioMedicine 6, 190–198 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Rolland, A. et al. The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J. Immunol. 176, 7636–7644 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Perron, H. et al. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult. Scler. 18, 1721–1736 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Mameli, G. et al. Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not human herpesvirus 6. J. Gen. Virol. 88, 264–274 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Garcia-Montojo, M. et al. The DNA copy number of human endogenous retrovirus-W (MSRV-type) is increased in multiple sclerosis patients and is influenced by gender and disease severity. PLoS ONE 8, e53623 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Porchet, H., Vidal, V., Kornmann, G., Malpass, S. & Curtin, F. A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env. Clin. Ther. 41, 1737–1746 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Curtin, F. et al. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin. Ther. 34, 2268–2278 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Kornmann, G. & Curtin, F. Temelimab, an IgG4 anti-human endogenous retrovirus monoclonal antibody: an early development safety review. Drug Saf. 43, 1287–1296 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Derfuss, T. et al. A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients–a twelve month follow-up. J. Neuroimmunol. 285, 68–70 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Derfuss, T. et al. A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients. Mult. Scler. 21, 885–893 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Hartung, H. P. et al. Efficacy and safety of temelimab in multiple sclerosis: results of a randomized phase 2b and extension study. Mult. Scler. 28, 429–440 (2022). This phase II clinical trial and extension did not meet its primary end point, but demonstrated possible beneficial effects of temelimab on MRI measures, suggesting less neuroaxonal destruction as well as less demyelination and/or improved remyelination.

    Article  CAS  PubMed  Google Scholar 

  138. Faissner, S., Plemel, J. R., Gold, R. & Yong, V. W. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat. Rev. Drug Discov. 18, 905–922 (2019).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Neurology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Ontario, Canada

    Jiwon Oh

  2. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

    Jiwon Oh

  3. Center for Neuroinflammation and Experimental Therapeutics, and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Amit Bar-Or

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The authors contributed equally to all aspects of the article.

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Correspondence to Amit Bar-Or.

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Competing interests

J.O. holds the Waugh Family Chair in MS Research and has received research funding from the Barford/Love MS Fund of St. Michael’s Hospital, Biogen-Idec, Brain Canada, EMD-Serono, the MS Society of Canada, the National MS Society, the National Institutes of Health, and Roche. She has received compensation for consulting or speaking from Biogen-Idec, BMS, EMD-Serono, Novartis, Roche and Sanofi-Genzyme. A.B.-O. holds the Melissa and Paul Anderson Chair. He has received research funding from the Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation, Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Foundation, the National Institutes of Health and the National MS Society. He has participated as a speaker in meetings sponsored by and received consulting fees from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi-Genzyme. He has received grant support to the University of Pennsylvania from Biogen Idec, Merck/EMD Serono, Novartis and Roche/Genentech.

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Nature Reviews Neurology thanks A. Bertolotto; D. Centonze, who co-reviewed with A. Gentile; and B. Weinstock-Guttman for their contribution to the peer review of this work.

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Oh, J., Bar-Or, A. Emerging therapies to target CNS pathophysiology in multiple sclerosis. Nat Rev Neurol 18, 466–475 (2022). https://doi.org/10.1038/s41582-022-00675-0

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