Neue Therapieansätze bei progredienter Multipler Sklerose

Simon Faissner; Ralf Gold

doi:10.1055/a-0880-0073

Fortschritte der Neurologie · Psychiatrie, Inhaltsverzeichnis

Fortschr Neurol Psychiatr 2019; 87(11): 653-671
DOI: 10.1055/a-0880-0073

Fort- und Weiterbildung

Neue Therapieansätze bei progredienter Multipler Sklerose

New therapeutic approaches in progressive multiple sclerosis

Simon Faissner

,

Ralf Gold

Abstract

Die Therapie der Multiplen Sklerose hat sich in den letzten Jahren durch die Entwicklung neuer Medikamente für die schubförmige Phase der Erkrankung umfangreich gewandelt. Die Entwicklung von Medikamenten für Progression war bisher hingegen weniger erfolgreich. Neue Substanzen umfassen den in Europa und den USA zugelassenen B-Zell depletierenden Antikörper Ocrelizumab, der bei primär progredienter MS mit Krankheitsaktivität zugelassen ist, sowie den Sphingosin-1-Phosphat Modulator Siponimod, der aktuell in der Zulassungsphase für sekundär-chronisch progrediente MS ist. Progression ist durch chronische Inflammation mit Aktivierung von T- und B-Zellen sowie Mikroglia mit Freisetzung reaktiver Sauerstoffmetabolite, altersabhängige Akkumulation von Eisen und damit einhergehend neuronaler Degeneration gekennzeichnet. In dieser Arbeit soll eine Übersicht über das Verständnis der Pathogenese und vielversprechende Therapieansätze für Progression in unterschiedlichen Stadien der Entwicklung gegeben werden.

Multiple sclerosis (MS) therapy made huge progress during the last years due to the development of new medications for the relapsing-remitting phase of the disease. The development of therapies for progressive MS was, however, less successful. New medications are the B-cell depleting antibody ocrelizumab, authorized for primary progressive MS with inflammatory activity and the sphingosine-1-receptor modulator siponimod, which is under development for secondary-progressive MS. Pathomechanisms of progressive MS comprise chronic inflammation with activation of T and B cells and microglia with release of reactive oxygen species, age-dependent accumulation of iron and neurodegeneration. In this review, we will discuss the knowledge about the pathogenesis of progression and potential therapeutic approaches in different stages of development.

Schlüsselwörter:

neurologische Erkrankung - Medikamentenzulassung - Zentralnervensystem - Neurodegeneration

Keywords

neurological disease - drug approval - central nervous system - neurodegeneration

Volltext

Referenzen

Literatur
1 Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012; 8: 647-656 . doi:10.1038/nrneurol.2012.168
2 Nikic I, Merkler D, Sorbara C. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature Med 2011; 17: 495-499 . doi:10.1038/nm.2324
3 Radbruch H, Bremer D, Guenther R. et al. Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE. Frontiers Immunol 2016; 7: 92 . doi:10.3389/fimmu.2016.00092
4 Chechneva OV, Mayrhofer F, Daugherty DJ. et al. Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol Dis 2011; 44: 63-72 . doi:10.1016/j.nbd.2011.06.004
5 Liu Y, Qin L, Li G. et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 2003; 305: 212-218 . doi:10.1124/jpet.102.043166
6 Mayo L, Trauger SA, Blain M. et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nature Med 2014; 20: 1147-1156 . doi:10.1038/nm.3681
7 Choi JW, Gardell SE, Herr DR. et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 2011; 108: 751-756 . doi:10.1073/pnas.1014154108
8 Lublin F, Miller DH, Freedman MS. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387 (10023): 1075-1084 . doi:10.1016/S0140-6736 (15)01314-8
9 Gentile A, Musella A, Bullitta S. et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammat 2016; 13: 207 . doi:10.1186/s12974-016-0686-4
10 Kappos L, Bar-Or A, Cree BAC. et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double- blind, randomised, phase 3 study. Lancet 2018; 391: 1263-1273 . doi:10.1016/s0140-6736(18)30475-6
11 Linker RA, Lee DH, Ryan S. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134: 678-692 . doi:10.1093/brain/awq386
12 Gross CC, Schulte-Mecklenbeck A, Klinsing S. et al. Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e183 . doi:10.1212/nxi.0000000000000183
13 Ghadiri M, Rezk A, Li R. et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e340 . doi:10.1212/nxi.0000000000000340
14 Fleischer V, Friedrich M, Rezk A. et al. Treatment response to dimethyl fumarate is characterized by disproportionate CD8 + T cell reduction in MS. Mult Scler 2018; 24: 632-641 . doi:10.1177/1352458517703799
15 Li R, Rezk A, Ghadiri M. et al. Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis. J Immunol 2017; 198: 691-698 . doi:10.4049/jimmunol.1601649
16 Parodi B, Rossi S, Morando S. et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol 2015; 130: 279-295 . doi:10.1007/s00401-015-1422-3
17 Strassburger-Krogias K, Ellrichmann G, Krogias C. et al. Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther Adv Neurol Disord 2014; 7: 232-238 . doi:10.1177/1756285614544466
18 Brundula V, Rewcastle NB, Metz LM. et al. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002; 125: 1297-1308
19 Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cellmicroglia interaction. J Leukocyte Biol 2005; 78: 135-143 . doi:10.1189/jlb.0804477
20 Metz LM, Li DKB, Traboulsee AL. et al. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med 2017; 376: 2122-2133 . doi:10.1056/NEJMoa1608889
21 Koch MW, Zabad R, Giuliani F. et al. Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. J Neurol Sci 2015; 358: 131-137 . doi:10.1016/j.jns.2015.08.1525
22 Faissner S, Mahjoub Y, Mishra M. et al. Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease? Mult Scler. 2017 . doi:10.1177/13524585 17728811 [ Epub ahead of print ]
23 Vermersch P, Benrabah R, Schmidt N. et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol 2012; 12: 36 . doi:10.1186/1471-2377-12-36
24 Howell OW, Reeves CA, Nicholas R. et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134: 2755-2771 . doi:10.1093/brain/awr182
25 Choi SR, Howell OW, Carassiti D. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 2012; 135: 2925-2937 . doi:10.1093/brain/aws189
26 Magliozzi R, Howell OW, Reeves C. et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68: 477-493 . doi:10.1002/ana.22230
27 Romme Christensen J, Bornsen L, Ratzer R. et al. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PloS One 2013; 8: e57820 . doi:10.1371/journal . pone.0057820
28 Hawker K, OʼConnor P, Freedman MS. et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66: 460-471 . doi:10.1002/ana.21867
29 Komori M, Lin YC, Cortese I. et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol 2016; 3: 166-179 . doi:10.1002/acn3.293
30 Montalban X, Hauser SL, Kappos L. et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376: 209-220 . doi:10.1056/NEJMoa1606468
31 Siders W, Wei R, Greene B. et al. GZ402668, a next-generation anti-CD52 antibody, displays decreased proinflammatory cytokine release in vitro. Neurology 2016; 86 ( 16 Supplement ): P3.068
32 Androdias G, Reynolds R, Chanal M. et al. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann Neurol 2010; 68: 465-476 . doi:10.1002/ana.22054
33 Komori M, Blake A, Greenwood M. et al. Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol 2015; 78: 3-20 . doi:10.1002/ana.24408
34 Kutzelnigg A, Lucchinetti CF, Stadelmann C. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705-2712 . doi:10.1093/brain/awh641
35 Rice CM, Mallam EA, Whone AL. et al. Safety and feasibility of autologous bone marrow cellular therapy in relapsing-progressive multiple sclerosis. Clin Pharmacol Ther 2010; 87: 679-685 . doi:10.1038/clpt.2010.44
36 Connick P, Kolappan M, Crawley C. et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012; 11: 150-156 . doi:10.1016/s1474-4422(11)70305-2
37 Mancardi GL, Sormani MP, Gualandi F. et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology 2015; 84: 981-988 . doi:10.1212/wnl.0000000000001329
38 Cull G, Hall D, Fabis-Pedrini MJ. et al. Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS. Mult Scler J Exp Transl Clin 2017; 3: 2055217317700167 . doi:10.1177/2055217317700167
39 Casanova B, Jarque I, Gascon F. et al. Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis. Neurol Sci 2017; 38: 1213-1221 . doi:10.1007/s10072-017-2933-6
40 Muraro PA, Pasquini M, Atkins HL. et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017; 74: 459-469 . doi:10.1001/jamaneurol.2016.5867
41 Trapp BD, Peterson J, Ransohoff RM. et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278-285 . doi:10.1056/NEJM199801293380502
42 Bitsch A, Schuchardt J, Bunkowski S. et al. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000; 123 (Pt 6): 1174-1183 . doi:10.1093/brain/123.6.1174
43 Sorbara CD, Wagner NE, Ladwig A. et al. Pervasive axonal transport deficits in multiple sclerosis models. Neuron 2014; 84: 1183-1190 . doi:10.1016/j.neuron.2014.11.006
44 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 U S A 2004; 101: 8168-8173 . doi:10.1073/pnas.0402765101
45 Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nature Clin Pract Neurol 2008; 4: 159-169 . doi:10.1038/ncpneuro0735
46 Paling D, Solanky BS, Riemer F. et al. Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain 2013; 136: 2305-2317 . doi:10.1093/brain/awt149
47 Kapoor R, Furby J, Hayton T. et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; 9: 681-688 . doi:10.1016/s1474-4422 (10)70131-9
48 Miller DH, Soon D, Fernando KT. et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007; 68: 1390-1401 . doi:10.1212/01 . wnl.0000260064.77700.fd
49 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. Nature Med 2007; 13: 1483-1489 . doi:10.1038/nm1668
50 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: 571-584 . doi:10.1093/brain/awq337
51 Arun T, Tomassini V, Sbardella E. et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain 2013; 136: 106-115 . doi:10.1093/brain/aws325
52 Gilgun-Sherki Y, Panet H, Melamed E. et al. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res 2003; 989: 196-204 . doi:10.1016/S0006-8993(03)03343-2
53 Kalkers NF, Barkhof F, Bergers E. et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 2002; 8: 532-533 . doi:10.1191/1352458502 ms849xx
54 Allaman I, Fiumelli H, Magistretti PJ. et al. Fluoxetine regulates the expression of neurotrophic / growth factors and glucose metabolism in astrocytes. Psychopharmacology 2011; 216: 75-84 . doi:10.1007/s00213-011-2190-y
55 Mostert JP, Sijens PE, Oudkerk M. et al. Fluoxetine increases cerebral white matter NAA / Cr ratio in patients with multiple sclerosis. Neurosci Lett 2006; 402: 22-24 . doi:10.1016/j.neulet . 2006.03.042
56 Mostert J, Heersema T, Mahajan M. et al. The effect of fluoxetine on progression in progressive multiple sclerosis: a doubleblind, randomized, placebo-controlled trial. ISRN Neurol 2013; 2013: 370943 . doi:10.1155/2013/370943
57 Black JA, Liu S, Hains BC. et al. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 2006; 129: 3196-3208 . doi:10.1093/brain/awl216
58 Raftopoulos R, Hickman SJ, Toosy A. et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 259-269 . doi:10.1016/s1474-4422(16)00004-1
59 Barkhof F, Hulst HE, Drulovic J. et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010; 74: 1033-1040 . doi:10.1212/WNL.0b013e3181d7d651
60 Fox RJ, Coffey CS, Cudkowicz ME. et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials 2016; 50: 166-177 . doi:10.1016/j . cct.2016.08.009
61 Fox RJ, Coffey CS, Conwit R. et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2018; 379: 846-855 . doi:10.1056/NEJMoa1803583
62 Chataway J, Schuerer N, Alsanousi A. et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebocontrolled, phase 2 trial. Lancet 2014; 383: 2213-2221 . doi:10.1016/s0140-6736(13)62242-4
63 Chan D, Binks S, Nicholas JM. et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol 2017; 16: 591-600 . doi:10.1016/s1474-4422(17)30113-8
64 Hametner S, Wimmer I, Haider L. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 2013; 74: 848-861 . doi:10.1002/ana.23974
65 Haider L, Simeonidou C, Steinberger G. et al. Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron. J Neurol Neurosurg Psychiat 2014; 85: 1386-1395 . doi:10.1136/jnnp-2014-307712
66 Faissner S, Mishra M, Kaushik DK. et al. Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nature Commun 2017; 8: 1990 . doi:10.1038/s41467-017-02119-6
67 Witte ME, Bo L, Rodenburg RJ. et al. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol 2009; 219: 193-204 . doi:10.1002/path.2582
68 Kiryu-Seo S, Ohno N, Kidd GJ. et al. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 2010; 30: 6658-6666 . doi:10.1523/jneurosci.5265-09.2010
69 Mahad DJ, Ziabreva I, Campbell G. et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009; 132: 1161-1174 . doi:10.1093/brain/awp046
70 Chamberlain KA, Chapey KS, Nanescu SE. et al. Creatine enhances mitochondrial-mediated oligodendrocyte survival after demyelinating injury. J Neurosci 2017; 37: 1479-1492 . doi:10.1523/jneurosci.1941-16.2016
71 Di Filippo M, Tozzi A, Tantucci M. et al. Interferon-beta1a protects neurons against mitochondrial toxicity via modulation of STAT1 signaling: electrophysiological evidence. Neurobiol Dis 2014; 62: 387-393 . doi:10.1016/j.nbd.2013.09.022
72 Leary SM, Miller DH, Stevenson VL. et al. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003; 60: 44-51
73 Kuhle J, Hardmeier M, Disanto G. et al. A 10-year follow-up of the European multicenter trial of interferon beta-1b in secondary-progressive multiple sclerosis. Mult Scler 2016; 22: 533-543 . doi:10.1177/1352458515594440
74 Tranah GJ, Santaniello A, Caillier SJ. et al. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology 2015; 85: 325-330 . doi:10.1212/WNL.0000000000001744
75 Joshi DC, Zhang CL, Lin TM. et al. Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS. J Neurosci 2015; 35: 5293-5306 . doi:10.1523/JNEUROSCI.3859-14.2015
76 Ruckh JM, Zhao JW, Shadrach JL. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 2012; 10: 96-103 . doi:10.1016/j.stem.2011.11.019
77 Mei F, Fancy SPJ, Shen YA. et al. Micropillar arrays as a highthroughput screening platform for therapeutics in multiple sclerosis. Nature Med 2014; 20: 954-960 . doi:10.1038/nm.3618
78 Mi S, Hu B, Hahm K. et al. LINGO‑1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nature Med 2007; 13: 1228-1233 . doi:10.1038/nm1664
79 Cadavid D, Balcer L, Galetta S. et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2017; 16: 189-199 . doi:10.1016/s1474-4422(16)30377-5
80 Tourbah A, Lebrun-Frenay C, Edan G. et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler 2016; 22: 1719-1731 . doi:10.1177/1352458516667568
81 Sedel F, Papeix C, Bellanger A. et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord 2015; 4: 159-169 . doi:10.1016/j . msard.2015.01.005
82 Gregg C, Shikar V, Larsen P. et al. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci 2007; 27: 1812-1823 . doi:10.1523/jneurosci.4441-06.2007
83 Zhornitsky S, Johnson TA, Metz LM. et al. Prolactin in combination with interferon-beta reduces disease severity in an animal model of multiple sclerosis. J Neuroinflammat 2015; 12: 55 . doi:10.1186/s12974-015-0278-8
84 Keough MB, Rogers JA, Zhang P. et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nature Commun 2016; 7: 11312 . doi:10.1038/ncomms11312
85 Lau LW, Keough MB, Haylock-Jacobs S. et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol 2012; 72: 419-432 . doi:10.1002/ana.23599
86 Sobel RA, Ahmed AS. White matter extracellular matrix chondroitin sulfate / dermatan sulfate proteoglycans in multiple sclerosis. J Neuropathol Exp Neurol 2001; 60: 1198-1207
87 Stoffels JM, de Jonge JC, Stancic M. et al. Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain 2013; 136: 116-131 . doi:10.1093/brain/aws313
88 Tepavcevic V, Kerninon C, Aigrot MS. et al. Early netrin-1 expression impairs central nervous system remyelination. Ann Neurol 2014; 76: 252-268 . doi:10.1002/ana.24201
89 Bin JM, Rajasekharan S, Kuhlmann T. et al. Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration. Am J Pathol 2013; 183: 673-680 . doi:10.1016/j.ajpath.2013.06.004
90 Plemel JR, Liu WQ, Yong VW. Remyelination therapies: a new direction and challenge inmultiple sclerosis. Nat Rev Drug Discov 2017; 16: 617-634 . doi:10.1038/nrd.2017.115
91 Kosa P, Ghazali D, Tanigawa M. et al. Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis treatment. Front Neurol 2016; 7: 131 . doi:10.3389/fneur.2016.00131
92 Green AJ, Gelfand JM, Cree BA. et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 2017; 390: 2481-2489 . doi:10.1016/s0140-6736(17)32346-2
93 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: e18 . doi:10.1212/nxi.0000000000000018