790
Views
4
CrossRef citations to date
0
Altmetric
Review

Remyelination therapies for multiple sclerosis: optimizing translation from animal models into clinical trials

, , ORCID Icon &

References

  • Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 2000;343(13):938–952.
  • Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–1517.
  • Orton S-M, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5(11):932–936.
  • Cree BA, Gourraud P-A, Oksenberg JR, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499–510.
  • Bermel RA, Rae-Grant AD, Fox RJ. Diagnosing multiple sclerosis at a later age: more than just progressive myelopathy. Mult Scler J. 2010;16(11):1335–1340.
  • Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med. 2018;378(2):169–180.
  • Nave K-A. Myelination and support of axonal integrity by glia. Nature. 2010;468(7321):244–252.
  • Franklin RJM, Ffrench-constant C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci. 2008;9(11):839–855.
  • Duncan ID, Radcliff AB, Heidari M, et al. The adult oligodendrocyte can participate in remyelination. Proc Nat Acad Sci. 2018;115(50):E11807.
  • Yeung MSY, Djelloul M, Steiner E, et al. Dynamics of oligodendrocyte generation in multiple sclerosis. Nature. 2019;566(7745):538–542.
  • Lucchinetti C, Brück W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707–717.
  • Popescu BFG, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum. 2013;19(4):901–921.
  • Metz I, Weigand SD, Popescu BFG, et al. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann Neurol. 2014;75(5):728–738.
  • Rodriguez M. Virus-induced demyelination in mice: “Dying Back” of oligodendrocytes. Mayo Clin Proc. 1985;60(7):433–438.
  • Breij EC, Brink BP, Veerhuis R, et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol. 2008;63(1):16–25.
  • Prineas JW, Parratt JD. Oligodendrocytes and the early multiple sclerosis lesion. Ann Neurol. 2012;72(1):18–31.
  • 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):710–721.
  • Kuhlmann T, Ludwin S, Prat A, et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13–24.
  • Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998;18(2):601.
  • Chang A, Nishiyama A, Peterson J, et al. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci. 2000;20(17):6404.
  • Wilson HC, Scolding NJ, Raine CS. Co-expression of PDGF α receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions. J Neuroimmunol. 2006;176(1):162–173.
  • Patrikios P, Stadelmann C, Kutzelnigg A, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain. 2006;129(12):3165–3172.
  • Nicaise AM, Wagstaff LJ, Willis CM, et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Nat Acad Sci. 2019;116(18):9030.
  • Jäkel S, Agirre E, Mendanha Falcão A, et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. 2019;566(7745):543–547.
  • Procaccini C, De Rosa V, Pucino V, et al. Animal models of Multiple Sclerosis. Eur J Pharmacol. 2015;759:182–191.
  • Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2017;133(2):223–244.
  • Bjelobaba I, Begovic-Kupresanin V, Pekovic S, et al. Animal models of multiple sclerosis: focus on experimental autoimmune encephalomyelitis. J Neurosci Res. 2018;96(6):1021–1042.
  • Burrows DJ, McGown A, Jain SA, et al. Animal models of multiple sclerosis: from rodents to zebrafish. Mult Scler J. 2018;25(3):306–324.
  • Vesterinen HM, Sena ES, Ffrench-constant C, et al. Improving the translational hit of experimental treatments in multiple sclerosis. Mult Scler J. 2010;16(9):1044–1055.
  • Piddlesden SJ, Lassmann H, Zimprich F, et al. The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol. 1993;143(2):555–564.
  • Mei F, Lehmann-Horn K, Shen Y-A-A, et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife. 2016;5:e18246.
  • Huseby ES, Liggitt D, Brabb T, et al. A pathogenic role for myelin-specific Cd8+ T cells in a model for multiple sclerosis. J Exp Med. 2001;194(5):669–676.
  • Saxena A, Bauer J, Scheikl T, et al. Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol. 2008;181(3):1617.
  • Lassmann H. Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci. 2003;206(2):187–191.
  • Sun D, Whitaker JN, Huang Z, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol. 2001;166(12):7579.
  • DePaula-Silva AB, Hanak TJ, Libbey JE, et al. Theiler’s murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: models for multiple sclerosis and epilepsy. J Neuroimmunol. 2017;308:30–42.
  • Katz-Levy Y, Neville KL, Girvin AM, et al. Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice. J Clin Invest. 1999;104(5):599–610.
  • Gerhauser I, Li L, Li D, et al. Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler’s murine encephalomyelitis virus. Apoptosis. 2018;23(2):170–186.
  • Raddatz BB, Sun W, Brogden G, et al. Central nervous system demyelination and remyelination is independent from systemic cholesterol level in Theiler’s murine encephalomyelitis. Brain Pathol. 2016;26(1):102–119.
  • Gerhauser I, Hansmann F, Ciurkiewicz M, et al. Facets of Theiler’s murine encephalomyelitis virus-induced diseases: an update. Int J Mol Sci. 2019;20(2):448.
  • Blakemore WF. The case for a central nervous system (CNS) origin for the Schwann cells that remyelinate CNS axons following concurrent loss of oligodendrocytes and astrocytes. Neuropathol Appl Neurobiol. 2005;31(1):1–10.
  • Hesse A, Wagner M, Held J, et al. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent. Neurobiol Dis. 2010;37(2):362–369.
  • Mason JL, Toews A, Hostettler JD, et al. Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am J Pathol. 2004;164(5):1673–1682.
  • Gudi V, Gingele S, Skripuletz T, et al. Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned. Front Cell Neurosci. 2014;8:73.
  • Kipp M, Nyamoya S, Hochstrasser T, et al. Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol. 2017;27(2):123–137.
  • Jäkel S, Dimou L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci. 2017;11:24.
  • Chow BM, Li YQ, Wong CS. Radiation-induced apoptosis in the adult central nervous system is p53-dependent. Cell Death Differ. 2000;7(8):712–720.
  • Kurita H, Kawahara N, Asai A, et al. Radiation-induced apoptosis of oligodendrocytes in the adult rat brain. Neurol Res. 2001;23(8):869–874.
  • Begolly S, Olschowka JA, Love T, et al. Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia. 2018;66(4):846–861.
  • Irvine K-A, Blakemore WF. A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue. Eur J Neurosci. 2007;25(2):417–424.
  • Irvine KA, Blakemore WF. Remyelination protects axons from demyelination-associated axon degeneration. Brain. 2008;131(6):1464–1477.
  • Chari DM, Blakemore WF. Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells. Glia. 2002;37(4):307–313.
  • Atkinson SL, Li Y-Q, Wong CS. Apoptosis and proliferation of oligodendrocyte progenitor cells in the irradiated rodent spinal cord. Int J Radiat Oncol Biol Phys. 2005;62(2):535–544.
  • Lumniczky K, Szatmári T, Sáfrány G. Ionizing radiation-induced immune and inflammatory reactions in the brain. Front Immunol. 2017;8:517.
  • Birey F, Aguirre A. Age-dependent netrin-1 signaling regulates NG2+ glial cell spatial homeostasis in normal adult gray matter. J Neurosci. 2015;35(17):6946.
  • Birey F, Kloc M, Chavali M, et al. Genetic and stress-induced loss of NG2 glia triggers emergence of depressive-like behaviors through reduced secretion of FGF2. Neuron. 2015;88(5):941–956.
  • Wright J, Zhang G, Yu T-S, et al. Age-related changes in the oligodendrocyte progenitor pool influence brain remodeling after injury. Dev Neurosci. 2010;32(5–6):499–509.
  • Hesp ZC, Yoseph RY, Suzuki R, et al. Proliferating NG2-cell-dependent angiogenesis and scar formation alter axon growth and functional recovery after spinal cord injury in mice. J Neurosci. 2018;38(6):1366.
  • Nakano M, Tamura Y, Yamato M, et al. NG2 glial cells regulate neuroimmunological responses to maintain neuronal function and survival. Sci Rep. 2017;7(1):42041.
  • Li R, Bernau K, Sandbo N, et al. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. Elife. 2018;7. DOI:10.7554/eLife.36865.
  • Robins SC, Villemain A, Liu X, et al. Extensive regenerative plasticity among adult NG2-glia populations is exclusively based on self-renewal. Glia. 2013;61(10):1735–1747.
  • Doetsch F, Caillé I, Lim DA, et al. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97(6):703–716.
  • Singer BH, Jutkiewicz EM, Fuller CL, et al. Conditional ablation and recovery of forebrain neurogenesis in the mouse. J Comp Neurol. 2009;514(6):567–582.
  • Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS One. 2009;4(5):e5464.
  • Kerezoudis P, Goyal A, Lu VM, et al. The role of radiation and chemotherapy in adult patients with high-grade brainstem gliomas: results from the national cancer database. J Neurooncol. 2020;146(2):303–310.
  • Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996.
  • Gibson EM, Nagaraja S, Ocampo A, et al. Methotrexate chemotherapy induces persistent Tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell. 2019;176(1–2):43–55.e13.
  • Wang S, Lai X, Deng Y, et al. Correlation between mouse age and human age in anti-tumor research: significance and method establishment. Life Sci. 2020;242:117242.
  • Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science. 2018;359(6376):684–688.
  • Neumann B, Baror R, Zhao C, et al. Metformin restores CNS remyelination capacity by rejuvenating aged stem cells. Cell Stem Cell. 2019;25(4):473–485.e8.
  • Rivera AD, Pieropan F, Chacon‐De‐La‐Rocha I, et al. Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum. Aging Cell. 2021;20(4):e13335.
  • Papadopoulos D, Magliozzi R, Mitsikostas DD, et al. Aging, cellular senescence, and progressive multiple sclerosis. Front Cell Neurosci. 2020;14:178.
  • Koutsoudaki PN, Papadopoulos D, Passias P-G, et al. Cellular senescence and failure of myelin repair in multiple sclerosis. Mech Ageing Dev. 2020;192:111366.
  • Zhang P, Kishimoto Y, Grammatikakis I, et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019;22(5):719–728.
  • Burns TC, Verfaillie CM. From mice to mind: strategies and progress in translating neuroregeneration. Eur J Pharmacol. 2015;759:90–100.
  • Burns TC, Li MD, Mehta S, et al. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: a systematic bioinformatics-based critique of preclinical models. Eur J Pharmacol. 2015;759:101-117.
  • Van Der Star BJ, Y.S. Vogel D, Kipp M, et al. In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets. 2012;11(5):570–588.
  • Eshaghi A, Young AL, Wijeratne PA, et al. Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data. Nat Commun. 2021;12(1):2078.
  • Tallantyre EC, Bø L, Al-Rawashdeh O, et al. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler. 2010;16(4):406–411.
  • Barkhof F, Calabresi PA, Miller DH, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5(5):256–266.
  • Steenwijk MD, Geurts JJG, Daams M, et al. Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant. Brain. 2016;139(Pt 1):115–126.
  • Fuchs TA, Carolus K, Benedict RHB, et al. Impact of focal white matter damage on localized subcortical gray matter atrophy in multiple sclerosis: a 5-year study. AJNR Am J Neuroradiol. 2018;39(8):1480–1486.
  • Petzold A, De Boer JF, Schippling S, et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010;9(9):921–932.
  • Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(11):2705–2712.
  • Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10(4):225–238.
  • Correale J, Marrodan M, Ysrraelit MC. Mechanisms of neurodegeneration and axonal dysfunction in progressive multiple sclerosis. Biomedicines. 2019;7(1):14.
  • Sherman LS, Back SA. A ‘GAG’ reflex prevents repair of the damaged CNS. Trends Neurosci. 2008;31(1):44–52.
  • Lau LW, Cua R, Keough MB, et al. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci. 2013;14(10):722–729.
  • Harlow DE, Macklin WB. Inhibitors of myelination: ECM changes, CSPGs and PTPs. Exp Neurol. 2014;251:39–46.
  • van Horssen J, Schreibelt G, Drexhage J, et al. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med. 2008;45(12):1729–1737.
  • Stoffels JM, de Jonge JC, Stancic M, et al. Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain. 2013;136(Pt 1):116–131.
  • Tremblay M, Stevens B, Sierra A, et al. The role of microglia in the healthy brain. J Neurosci. 2011;31(45):16064–16069.
  • Ueno M, Fujita Y, Tanaka T, et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci. 2013;16(5):543–551.
  • Liu YU, Ying Y, Li Y, et al. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat Neurosci. 2019;22(11):1771–1781.
  • Umpierre AD, Bystrom LL, Ying Y, et al. Microglial calcium signaling is attuned to neuronal activity in awake mice. Elife. 2020;9. DOI:10.7554/eLife.56502.
  • Hughes AN, Appel B. Microglia phagocytose myelin sheaths to modify developmental myelination. Nat Neurosci. 2020;23(9):1055–1066.
  • Hagemeyer N, Hanft K-M, Akriditou M-A, et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 2017;134(3):441–458.
  • Voet S, Prinz M, Van Loo G. Microglia in central nervous system inflammation and multiple sclerosis pathology. Trends Mol Med. 2019;25(2):112–123.
  • Lloyd AF, Miron VE. The pro-remyelination properties of microglia in the central nervous system. Nat Rev Neurol. 2019;15(8):447–458.
  • Guerrero BL, Sicotte NL. Microglia in multiple sclerosis: friend or Foe? Front Immunol. 2020;11:374.
  • Zia S, Rawji KS, Michaels NJ, et al. Microglia diversity in health and multiple sclerosis. Front Immunol. 2020;11:588021.
  • Li MD, Burns TC, Kumar S, et al. Aging-like changes in the transcriptome of irradiated microglia. Glia. 2015;63(5):754–767.
  • Rawji KS, Gonzalez Martinez GA, Sharma A, et al. The role of astrocytes in remyelination. Trends Neurosci. 2020;43(8):596–607.
  • Domingues HS, Portugal CC, Socodato R, et al. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol. 2016;4:71-87.
  • Dong Y, Yong VW. When encephalitogenic T cells collaborate with microglia in multiple sclerosis. Nat Rev Neurol. 2019;15(12):704–717.
  • Pennati A, Nylen EA, Duncan ID, et al. Regulatory B cells normalize CNS myeloid cell content in a mouse model of multiple sclerosis and promote oligodendrogenesis and remyelination. J Neurosci. 2020;40(26):5105–5115.
  • Goldman SA, Nedergaard M, Windrem MS. Modeling cognition and disease using human glial chimeric mice. Glia. 2015;63(8):1483–1493.
  • Windrem MS, Schanz SJ, Morrow C, et al. A competitive advantage by neonatally engrafted human glial progenitors yields mice whose brains are chimeric for human glia. J Neurosci. 2014;34(48):16153–16161.
  • Mei F, Fancy SPJ, Shen Y-A-A, et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014;20(8):954–960.
  • Li Z, He Y, Fan S, et al. Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination. Neurosci Bull. 2015;31(5):617–625.
  • Welliver RR, Polanco JJ, Seidman RA, et al. Muscarinic receptor M3R signaling prevents efficient remyelination by human and mouse oligodendrocyte progenitor cells. J Neurosci. 2018;38(31):6921.
  • Larocca JN, Almazan G. Acetylcholine agonists stimulate mitogen-activated protein kinase in oligodendrocyte progenitors by muscarinic receptors. J Neurosci Res. 1997;50(5):743–754.
  • De Angelis F, Bernardo A, Magnaghi V, et al. Muscarinic receptor subtypes as potential targets to modulate oligodendrocyte progenitor survival, proliferation, and differentiation. Dev Neurobiol. 2012;72(5):713–728.
  • 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(10111):2481–2489.
  • Assessment of clemastine fumarate as a remyelinating agent in acute optic neuritis (ReCOVER). [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT02521311
  • Fujimoto K, Mizuguchi H, Fukui H, et al. Presynaptic localization of histamine H3-receptors in rat brain. Biochem Biophys Res Commun. 1991;177(3):907–912.
  • Chen Y, Zhen W, Guo T, et al. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. PLOS ONE. 2017;12(12):e0189380.
  • Rangon C-M, Schang A-L, Van Steenwinckel J, et al. Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury. Brain Behav Immun. 2018;74:265–276.
  • Schwartzbach CJ, Grove RA, Brown R, et al. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017;264(2):304–315.
  • Bordet T, Berna P, Abitbol J-L, et al. Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals. 2010;3(2):345–368.
  • Magalon K, Zimmer C, Cayre M, et al. Olesoxime accelerates myelination and promotes repair in models of demyelination. Ann Neurol. 2012;71(2):213–226.
  • Magalon K, Le Grand M, El Waly B, et al. Olesoxime favors oligodendrocyte differentiation through a functional interplay between mitochondria and microtubules. Neuropharmacology. 2016;111:293–303.
  • Li Y, Zhang Y, Han W, et al. TRO19622 promotes myelin repair in a rat model of demyelination. Int J Neurosci. 2013;123(11):810–822.
  • Pelletier J, Ranjeva J-P,  Tourbah A, et al. Results of a Phase 1b study to confirm safety and tolerability of olesoxime in multiple sclerosis patients (P7.282). Neurology. 2015;84(14 Supplement): P7.282.
  • Safety study of olesoxime in patients with stable relapsing remitting multiple sclerosis treated with interferon beta. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT01808885
  • Huang JK, Jarjour AA, Nait Oumesmar B, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45–53.
  • Chiang ACA, Seua AV, Singhmar P, et al. Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice. Acta Neuropathol Commun. 2020;8(1):193.
  • A randomised placebo-controlled study of the safety and tolerability of a retinoid-X receptor agonist’s ability to promote remyelination in people with relapsing-remitting multiple sclerosis already on interferon-beta therapy: a phase 2a trial. [cited 2021 Apr 28]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-003145-99/GB
  • Shen X, Liu W, Gao X, et al. Mechanisms of oxidase and superoxide dismutation-like activities of Gold, Silver, Platinum, and Palladium, and their alloys: a general way to the activation of molecular oxygen. J Am Chem Soc. 2015;137(50):15882–15891.
  • Fünfschilling U, Supplie LM, Mahad D, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485(7399):517–521.
  • Robinson AP, Zhang JZ, Titus HE, et al. Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis. Sci Rep. 2020;10(1):1936.
  • Aghaie T, Jazayeri MH, Avan A, et al. Gold nanoparticles and polyethylene glycol alleviate clinical symptoms and alter cytokine secretion in a mouse model of experimental autoimmune encephalomyelitis. IUBMB Life. 2019;71(9):1313–1321.
  • Nanocrystalline Gold to treat remyelination failure in chronic optic neuropathy in multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT03536559
  • A multi-center, open-label long-term extension study of CNM-Au8 in patients with stable relapsing multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT04626921
  • Zhornitsky S, Yong VW, Weiss S, et al. Prolactin in multiple sclerosis. Mult Scler J. 2012;19(1):15–23.
  • De Giglio L, Marinelli F, Prosperini L, et al. Relationship between prolactin plasma levels and white matter volume in women with multiple sclerosis. Mediators Inflamm. 2015;2015:732539.
  • Gregg C, Shikar V, Larsen P, et al. White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci. 2007;27(8):1812.
  • Correale J, Farez MF, Ysrraelit MC. Role of prolactin in B cell regulation in multiple sclerosis. J Neuroimmunol. 2014;269(1):76–86.
  • Costanza M, Pedotti R. Prolactin: friend or Foe in central nervous system autoimmune inflammation? Int J Mol Sci. 2016;17(12):2026.
  • Koch MW, Liu W-Q, Camara-Lemarroy C, et al. Domperidone-induced elevation of serum prolactin levels and immune response in multiple sclerosis. J Neuroimmunol. 2019;334:576974.
  • Chandran P, Upadhyay J, Markosyan S, et al. Magnetic resonance imaging and histological evidence for the blockade of cuprizone-induced demyelination in C57BL/6 mice. Neuroscience. 2012;202:446–453.
  • Wang H-N, Liu G-H, Zhang R-G, et al. Quetiapine ameliorates schizophrenia-like behaviors and protects myelin integrity in cuprizone intoxicated mice: the involvement of notch signaling pathway. Int J Neuropsychopharmacol. 2016;19(2): pyv088.
  • Xu H, Yang H, McConomy B, et al. Behavioral and neurobiological changes in C57BL/6 mouse exposed to cuprizone: effects of antipsychotics. Front Behav Neurosci. 2010;4:8.
  • Zhang Y, Zhang H, Wang L, et al. Quetiapine enhances oligodendrocyte regeneration and myelin repair after cuprizone-induced demyelination. Schizophr Res. 2012;138(1):8–17.
  • Mei F, Guo S, He Y, et al. Quetiapine, an atypical antipsychotic, is protective against autoimmune-mediated demyelination by inhibiting effector T cell proliferation. PLOS ONE. 2012;7(8):e42746.
  • Bi X, Zhang Y, Yan B, et al. Quetiapine prevents oligodendrocyte and myelin loss and promotes maturation of oligodendrocyte progenitors in the hippocampus of global cerebral ischemia mice. J Neurochem. 2012;123(1):14–20.
  • Xiao L, Xu H, Zhang Y, et al. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry. 2008;13(7):697–708.
  • Xu H, Yang H-J, Li X-M. Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone. Eur Arch Psychiatry Clin Neurosci. 2014;264(2):121–129.
  • Gonzalez Cardona J, Smith MD, Wang J, et al. Quetiapine has an additive effect to triiodothyronine in inducing differentiation of oligodendrocyte precursor cells through induction of cholesterol biosynthesis. PLOS ONE. 2019;14(9):e0221747.
  • Safety and tolerability of quetiapine in multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT02087631
  • Tsai PT, Ohab JJ, Kertesz N, et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci. 2006;26(4):1269.
  • Nagai A, Nakagawa E, Choi HB, et al. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol. 2001;60(4):386–392.
  • Sugawa M, Sakurai Y, Ishikawa-Ieda Y, et al. Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res. 2002;44(4):391–403.
  • Mirzaie J, Raoofi A, Jamalpoor Z, et al. Protective impacts of erythropoietin on myelinization of oligodendrocytes and schwann cells in CNS and PNS following cuprizone-induced multiple sclerosis- histology, molecular, and functional studies. J Chem Neuroanat. 2020;104:101750.
  • Mustapha O, Oke B, Offen N, et al. Neurobehavioral and cytotoxic effects of vanadium during oligodendrocyte maturation: a protective role for erythropoietin. Environ Toxicol Pharmacol. 2014;38(1):98–111.
  • Genc K, Genc S, Baskin H, et al. Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes. Physiol Res. 2006;55(1):33–38.
  • Moransard M, Bednar M, Frei K, et al. Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. J Neuroinflammation. 2017;14(1):202.
  • Li W, Maeda Y, Yuan RR, et al. Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol. 2004;56(6):767–777.
  • Zhang J, Li Y, Cui Y, et al. Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain Res. 2005;1034(1):34–39.
  • Cho YK, Kim G, Park S, et al. Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture. Biochem Biophys Res Commun. 2012;417(2):753–759.
  • Sühs K-W, Hein K, Sättler MB, et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol. 2012;72(2):199–210.
  • Diem R, Molnar F, Beisse F, et al. Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial—study protocol. BMJ Open. 2016;6(3):e010956.
  • Treatment of optic neuritis with erythropoietin: a randomised, double-blind, placebo-controlled trial. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT01962571
  • Schreiber K, Magyari M, Sellebjerg F, et al. High-dose erythropoietin in patients with progressive multiple sclerosis: a randomized, placebo-controlled, phase 2 trial. Mult Scler J. 2016;23(5):675–685.
  • Abi Ghanem C, Degerny C, Hussain R, et al. Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor. PLoS Genet. 2017;13(11):e1007049.
  • Cerghet M, Skoff RP, Bessert D, et al. Proliferation and death of oligodendrocytes and myelin proteins are differentially regulated in male and female rodents. J Neurosci. 2006;26(5):1439.
  • Hussain R, Ghoumari AM, Bielecki B, et al. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. Brain. 2013;136(1):132–146.
  • DonCarlos LL, Sarkey S, Lorenz B, et al. Novel cellular phenotypes and subcellular sites for androgen action in the forebrain. Neuroscience. 2006;138(3):801–807.
  • Bielecki B, Mattern C, Ghoumari AM, et al. Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin. Proc Nat Acad Sci. 2016;113(51):14829.
  • Sicotte NL, Giesser BS, Tandon V, et al. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007;64(5):683–688.
  • Metzger-Peter K, Kremer LD, Edan G, et al. The TOTEM RRMS (Testosterone treatment on neuroprotection and myelin repair in relapsing remitting multiple sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial. Trials. 2020;21(1):591.
  • Voskuhl RR, Gold SM. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol. 2012;8(5):255–263.
  • Tiwari-Woodruff S, Morales LBJ, Lee R, et al. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment. Proc Nat Acad Sci. 2007;104(37):14813.
  • Rankin KA, Mei F, Kim K, et al. Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors. J Neurosci. 2019;39(12):2184.
  • Hubler Z, Allimuthu D, Bederman I, et al. Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination. Nature. 2018;560(7718):372–376.
  • Voskuhl RR, Itoh N, Tassoni A, et al. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Nat Acad Sci. 2019;116(20):10130.
  • Bazedoxifene acetate as a remyelinating agent in multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT04002934
  • Vaginal estriol in multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT03774407
  • Lee JY, Petratos S. Thyroid hormone signaling in oligodendrocytes: from extracellular transport to intracellular signal. Mol Neurobiol. 2016;53(9):6568–6583.
  • Fernandez M, Giuliani A, Pirondi S, et al. Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. Proc Natl Acad Sci U S A. 2004;101(46):16363.
  • D’Intino G, Lorenzini L, Fernandez M, et al. Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism. J Neuroendocrinol. 2011;23(9):778–790.
  • Harsan L-A, Steibel J, Zaremba A, et al. Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging. J Neurosci. 2008;28(52):14189.
  • Castelo-Branco G, Stridh P, Guerreiro-Cacais AO, et al. Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats. Neurobiol Dis. 2014;71:220–233.
  • Wooliscroft L, Altowaijri G, Hildebrand A, et al. Phase I randomized trial of liothyronine for remyelination in multiple sclerosis: a dose-ranging study with assessment of reliability of visual outcomes. Mult Scler Relat Disord. 2020;41:102015.
  • Jepson S, Vought B, Gross CH, et al. LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions. J Biol Chem. 2012;287(26):22184–22195.
  • Zhao X-H, Jin W-L, Ju G. An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells. Mol Cell Neurosci. 2007;36(2):260–269.
  • 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.
  • 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):1228–1233.
  • 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 Neuroinflammat. 2014;1(2):e18.
  • 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(3):189–199.
  • Cadavid D, Mellion M, Hupperts R, et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019;18(9):845–856.
  • BIIB033 in acute optic neuritis (AON). [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT01721161
  • Long-term assessment of remyelinating therapy. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT02657915
  • Okuno T, Nakatsuji Y, Kumanogoh A. The role of immune semaphorins in multiple sclerosis. FEBS Lett. 2011;585(23):3829–3835.
  • Yamaguchi W, Tamai R, Kageura M, et al. Sema4D as an inhibitory regulator in oligodendrocyte development. Mol Cell Neurosci. 2012;49(3):290–299.
  • Giraudon P, Vincent P, Vuaillat C, et al. Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. J Immunol. 2004;172(2):1246.
  • Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015;73:254–268.
  • LaGanke C, Samkoff L, Edwards K, et al. Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. Neurol Neuroimmunol Neuroinflammat. 2017;4(4):e367.
  • Rajagopalan S, Deitinghoff L, Davis D, et al. Neogenin mediates the action of repulsive guidance molecule. Nat Cell Biol. 2004;6(8):756–762.
  • Siebold C, Yamashita T, Monnier PP, et al. RGMs: structural insights, molecular regulation, and downstream signaling. Trends Cell Biol. 2017;27(5):365–378.
  • Muramatsu R, Kubo T, Mori M, et al. RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis. Nat Med. 2011;17(4):488–494.
  • Tanabe S, Yamashita T. Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis. Cell Rep. 2014;9(4):1459–1470.
  • Demicheva E, Cui Y-F, Bardwell P, et al. Targeting repulsive guidance molecule a to promote regeneration and neuroprotection in multiple sclerosis. Cell Rep. 2015;10(11):1887–1898.
  • Tanabe S, Fujita Y, Ikuma K, et al. Inhibiting repulsive guidance molecule-a suppresses secondary progression in mouse models of multiple sclerosis. Cell Death Dis. 2018;9(11):1061.
  • Ziemann A, Rosebraugh M, Barger B, et al. A Phase 1, multiple-dose study of Elezanumab (ABT-555) in patients with relapsing forms of multiple sclerosis (S56.001). Neurology. 2019;92(15 Supplement):S56.001.
  • A study to assess the safety and efficacy of Elezanumab when added to standard of care in progressive forms of multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT03737812
  • Mitsunaga Y, Ciric B, Van Keulen V, et al. Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J. 2002;16(10):1325–1327.
  • Pirko I, Ciric B, Gamez J, et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J. 2004;18(13):1577–1579.
  • Bieber AJ, Warrington A, Asakura K, et al. Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia. 2002;37(3):241–249.
  • Mullin AP, Cui C, Wang Y, et al. rHIgM22 enhances remyelination in the brain of the cuprizone mouse model of demyelination. Neurobiol Dis. 2017;105:142–155.
  • Cui C, Wang J, Mullin AP, et al. The antibody rHIgM22 facilitates hippocampal remyelination and ameliorates memory deficits in the cuprizone mouse model of demyelination. Brain Res. 2018;1694:73–86.
  • Warrington AE, Asakura K, Bieber AJ, et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Nat Acad Sci. 2000;97(12):6820.
  • Warrington AE, Bieber AJ, Ciric B, et al. A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res. 2007;85(5):967–976.
  • Vala M, Jordan LR, Warrington AE, et al. Surface plasmon resonance sensing on naturally derived membranes: a remyelination-promoting human antibody binds myelin with extraordinary affinity. Anal Chem. 2018;90(21):12567–12573.
  • Watzlawik JO, Warrington AE, Rodriguez M. PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLOS ONE. 2013;8(2):e55149.
  • Howe CL, Bieber AJ, Warrington AE, et al. Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis. 2004;15(1):120–131.
  • Eisen A, Greenberg BM, Bowen JD, et al. A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. Multiple Sclerosis Journal – Experimental Transl Clin. 2017;3(4):2055217317743097.
  • An intravenous infusion study of rHIgM22 in patients with multiple sclerosis immediately following a relapse. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT02398461
  • Derfuss T, Mehling M, Papadopoulou A, et al. Advances in oral immunomodulating therapies in relapsing multiple sclerosis. Lancet Neurol. 2020;19(4):336–347.
  • Windrem MS, Schanz SJ, Zou L, et al. Human glial progenitor cells effectively remyelinate the demyelinated adult brain. Cell Rep. 2020;31(7):107658.
  • A study to assess the safety and efficacy of Elezanumab when added to standard of care in relapsing forms of multiple sclerosis. [cited 2021 Apr 28]. Available from: https://ClinicalTrials.gov/show/NCT03737851
  • Wootla B, Denic A, Watzlawik JO, et al. Antibody-mediated oligodendrocyte remyelination promotes axon health in progressive demyelinating disease. Mol Neurobiol. 2016;53(8):5217–5228.
  • Butt AM, De La Rocha IC, Rivera A. Oligodendroglial cells in Alzheimer’s disease. Adv Exp Med Biol. 2019;1175:325–333.
  • Conway BL, Zeydan B, Uygunoğlu U, et al. Age is a critical determinant in recovery from multiple sclerosis relapses. Mult Scler. 2019;25(13):1754–1763.
  • Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci. 2018;21(5):683–695.
  • Long P, Corfas G. Neuroscience. To learn is to myelinate. Science. 2014;346(6207):298–299.
  • McKenzie IA, Ohayon D, Li H, et al. Motor skill learning requires active central myelination. Science. 2014;346(6207):318–322.
  • Xiao L, Ohayon D, McKenzie IA, et al. Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. Nat Neurosci. 2016;19(9):1210–1217.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.