By Sandy Hayes, PhD
Multiple sclerosis (MS) is a degenerative neurological disease in which cells of the immune system invade and attack the central nervous system (CNS). A major target of this attack is myelin, the protective insulation surrounding axons (nerve fibers) that facilitates the rapid transmission of nerve impulses within the CNS and throughout the body.1 Without this myelin sheath, axonal function and survival steadily decrease with time.1 This gradual deterioration in neurological function, termed neurodegeneration, leads to the appearance of such symptoms as numbness, loss of balance, slurred speech, blurred vision, impaired mobility, and even paralysis.2
The clinical presentations or physical symptoms associated with MS are diverse and vary throughout the course of the disease. Relapsing-remitting MS (RRMS) represents 85% of all newly diagnosed patients and is the most prevalent form of MS.3 As its name indicates, RRMS is characterized by alternating periods of symptomatic flares (relapses) and complete or partial recovery (remissions). With time, RRMS patients experience a steady worsening of their neurological symptoms, marking their transition to a neurodegenerative phase of the disease known as secondary-progressive MS (SPMS).4 The other 15% of new MS patients are diagnosed with either primary-progressive MS (PPMS) or progressive-relapsing MS (PRMS).4 The disease process in PPMS and PRMS patients begins with a neurodegenerative phase, but PRMS patients experience relapses similar to those experienced by RRMS patients.4
Currently, disease-modifying therapies (DMTs) are the standard treatment for relapsing forms of MS; no FDA-approved treatment options exist for PPMS.5–8 DMTs act to restrain the overactive immune system and to prevent new immune-mediated attacks on myelinated axons. Although DMTs lessen symptom severity and increase the time between symptomatic flares, they do not halt the progression of neurologic disability, as DMTs do not improve the function and survival of demyelinated axons.9 To counteract progressive neurodegeneration, researchers are investigating whether stimulation of an MS patient’s myelin repair machinery remyelinates axons and restores axonal function.
Incomplete myelin repair in MS patients
Myelin repair is dependent on the actions of CNS-resident oligodendrocyte precursor cells (OPCs) and their descendants, oligodendrocytes.10 OPCs are recruited to the sites of axon demyelination, where they begin a differentiation program that leads to their maturation into myelinating oligodendrocytes. Once formed, the mature oligodendrocytes not only spirally wrap axons with myelin but also provide nutrients that support axonal survival (Figure 1).11,12
Figure 1. Demyelination and loss of myelinating oligodendrocytes leads to axonal degeneration in MS. (A)
Because of its ability to insulate, myelin allows the swift relay of information along the length of the axon, through the axon terminal, to either a neighboring neuron (nerve cell) or a target cell (eg, muscle cell). (B) When the axon is stripped of its myelin, as in MS, this relay is slowed, interrupted, or distorted. (C) In the absence of mature oligodendrocytes, which form myelin and provide nutritional support, axons are vulnerable to injury, degradation, and loss.
Technological advances in brain imaging allow researchers to measure the amount of myelin in the white matter of the brain, where myelinated axons localize.13 Analysis of such images from SPMS patients showed multiple cycles of demyelination and remyelination at the same sites within the white matter, but remyelination was less complete after each round of demyelination.13
Examination of postmortem brain tissue from MS patients has provided insight into why remyelination is incomplete in MS. In studies that quantitated OPCs and mature oligodendrocytes at sites of demyelination, it was found that approximately 30% of the sites had reduced numbers of OPCs. The remaining sites, on the other hand, had normal numbers of OPCs, but these cells were arrested in an undifferentiated state.14,15 Together, these data suggest that the reduced capacity of MS patients to repair myelin is because of impaired migration of OPCs to the site of demyelination or because of impaired maturation of OPCs into myelinating oligodendrocytes.14–16
Identifying druggable targets in the myelin repair or remyelination pathway
To stimulate myelin repair or remyelination in MS patients, researchers are focusing on approaches that promote OPC migration, survival, and maturation. The past several years of research have produced a number of druggable targets, which fall into two broad categories: molecules that negatively regulate OPC function and molecules that positively regulate OPC function (Table 1).
|Target1||References||Potential therapeutic drug||Clinical trial2|
|LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1)||19-21||Anti-LINGO-1 antibody
|24||ET receptor antagonist
|Oxidative stress||27||Mitochondria-targeted anti-oxidant Mitoquinone (MitoQ)||Not for MS
Phase 2 for Parkinson’s Disease
|CXCR2||28||Small molecule CXCR2 antagonist||No|
FDA-approved drug to treat hypertension
(Myelin Repair Foundation)
|Clinical trial in partnership with the NIH|
|Estrogen receptor||30,31||Estrogen receptor ligands
|Acetyl-CoA carboxylases (ACC1 and ACC2)||34,35||High-dose D-biotin
|Platelet-derived growth factor receptor alpha (PDGFαR)||36,37||Recombinant human remyelination promoting IgM rHIgM22
1Targets that are negative regulators of OPC function are highlighted in red, whereas those that are positive regulators are highlighted in green. How MRF-008 affects OPC function has not been disclosed; it is highlighted in white.
2Information obtained from ClinicalTrials.gov.
Although several targets have been identified in the myelin repair pathway, only six of them have potential therapeutic drugs that are being evaluated in clinical trials (Table 1). Two prospective therapeutic drugs are antibody antagonists, which block the activity of Semaphorin 4D (Sema4D) and LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1), both of which are negative regulators of OPC migration and maturation.17–21 Treating rodent models of demyelination with either the anti-Sema4D antibody or the anti-LINGO-1 antibody resulted in significant increases in the number of OPCs at demyelination sites and in the extent of remyelination compared to control-treated rodents.18–19 The anti-Sema4D antibody is currently being tested for safety and tolerability in a phase 1 trial while the anti-LINGO-1 antibody demonstrated tolerability and is now being tested in a phase 2 trial for safety and efficacy.
Recombinant human IgM (rHIgM22) is another antibody in clinical trials as a potential therapeutic drug for myelin repair; however, it acts as an agonist, not an antagonist. rHIgM22 binds and activates platelet-derived growth factor receptor alpha, a cell surface protein that provides OPCs with a signal to proliferate or increase in number.37 In a virus-induced model of demyelination, rHIgM22 treatment significantly increased the level of remyelination (59.7%) in relation to control treatment (15.8%).36 Phase 1 trials are underway to evaluate the safety and tolerability of rHIgM22.
Another druggable target in the myelin repair pathway is acetyl-CoA carboxylase, a biotin-dependent enzyme that synthesizes the fatty acids needed to produce myelin.34 High-dose biotin (MD1003), through its ability to enhance myelin lipid synthesis in oligodendrocytes, improved neurological symptoms in almost 90% (20/23) of the MS patients enrolled in a small, open-label study.34,35 Because of these findings, MD1003 has moved to a phase 3 trial.
The last two potential therapeutic drugs for myelin repair are drugs that are already in use to treat other medical conditions. MRF-008 is a generic drug for hypertension whose target in the remyelination pathway has not been disclosed.29 MRF-008 will be tested as a remyelination drug in a clinical trial in partnership with the National Institutes of Health.29 The other “repurposed” drug is clemastine (Tavist), an antihistamine that blocks both histamine and muscarinic receptors and that is used to treat allergies. Clemastine was identified in a high-throughput screen of 1000 compounds for its ability to induce OPC differentiation and oligodendrocyte myelination in culture.25 Its ability to promote remyelination was also assayed in a mouse demyelination model. This experiment showed that clemastine-treatment significantly increased both the kinetics and the extent of remyelination compared to control treatment.25 The effectiveness of clemastine as a remyelination drug is currently being evaluated in a phase 2 trial.
The combination of innovative thinking and new technology has led to the discovery of multiple strategies to remyelinate axons in MS patients. Within the next five years, after the completion of the clinical trials, we will know whether these remyelination strategies halt and possibly correct neurodegeneration. Because all forms of MS share a neurodegenerative phase, the results of these clinical trials may lead to therapeutic options for all patients with MS.
- National Multiple Sclerosis Society: Definition of MS.
http://www.nationalmssociety.org/What-is-MS/Definition-of-MS. Accessed January 28, 2015.
- National Multiple Sclerosis Society: MS Symptoms.
http://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms. Accessed January 28, 2015.
- National Multiple Sclerosis Society: Relapsing-remitting MS (RRMS).
http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Relapsing-remitting-MS. Accessed January 28, 2015.
- National Multiple Sclerosis Society: Types of MS.
http://www.nationalmssociety.org/What-is-MS/Types-of-MS. Accessed January 28, 2015.
- National Multiple Sclerosis Society: Treating RRMS.
http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Relapsing-remitting-MS/Treatment-(1). Accessed January 28, 2015.
- National Multiple Sclerosis Society: Treating SPMS.
http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS/Treating-Secondary-Progressive-MS. Accessed January 28, 2015.
- National Multiple Sclerosis Society: Treating PPMS.
http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Primary-progressive-MS/Treating-Primary-Progressive-MS. Accessed January 28, 2015.
- National Multiple Sclerosis Society: Treating PRMS.
http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Progressive-relapsing-MS/Treating-Progressive-Relapsing-MS. Accessed January 28, 2015.
- Compston A, Coles A. Multiple Sclerosis. Lancet. 2008;372:1502-1517.
- Gensert JM, Goldman JE. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron. 1997;19:197-203.
- Funfschilling U, Supplie LM, Mahad D, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485:517-521.
- Lee Y, Morrison BM, Li Y, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012;487:443-448.
- Brown RA, Narayana S, Arnold DL. Imaging of repeated episodes of demyelination and remyelination in multiple sclerosis. NeuroImage: Clinical 2014;6:20-25.
- Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 1999;122:2279-2295.
- Boyd A, Zhang H, Williams A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol 2013;125:841-859.
- Williams A. Central nervous system regeneration – where are we? Q J Med. 2014;107:335-339.
- Taniguchi Y, Amazaki M, Furuyama T, et al. Sema4D deficiency results in an increase in the number of oligodendrocytes in healthy and injured mouse brains. J Neurosci Res. 2009;87:2833-2841.
- Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2014;73C:254-268.
- 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;13:1228-1233.
- 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;287:22184-22195.
- 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.
- Syed YA, Hand E, Möbius W, et al. Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci. 2011;31:3719-3728.
- Piaton G, Aigrot MS, Williams A, et al. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain. 2011;134:1156-1167.
- Hammond TR, Gadea A, Dupree J, et al. Astrocyte-derived endothelin-1 inhibits remyelination through notch activation. Neuron. 2014;81:588-602.
- Mei F, Fancy SP, Shen YA, et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014;20:954-960.
- Deshmukh VA, Tardif V, Lyssiotis CA, et al. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013;502:327-332.
- Mao P, Manczak M, Shirendeb UP, Reddy PH. MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochim Biophys Acta. 2013;1832:2322-2331.
- Liu L, Darnall L, Hu T, Choi K, Lane TE, Ransohoff RM. Myelin repair is accelerated by inactivating CXCR2 on nonhematopoietic cells. J Neurosci. 2010;30:9074-9083.
- Myelin Repair Foundation: MRF-008: Potential MS drug to protect and repair myelin.
http://www.myelinrepair.org/mrf-008.shtml. Accessed on January 28, 2015.
- Nye SH, Babine RE, Xu W, Bittner M, Trapp BD, Yarger JG. NDC-1308: An estrogen receptor ligand that induces demyelination in MS models. ACTRIMS. Abstract presented June 1, 2013.
- Moore SM, Khalaj AJ, Kumar S, et al. Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis. Proc Natl Acad Sci U S A. 2014;111:18061-18066.
- Çolakoğlu G, Bergstrom-Tyrberg U, Berglund EO, Ranscht B. Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system. Proc Natl Acad Sci U S A. 2014;111:E394-403.
- Huang JK, Jarjour AA, Nait Oumesmar B, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14:45-53.
- medDay Pharmaceuticals: MD1003.
http://www.medday-pharma.com/research-development/pipeline/md1003/. Accessed on January 28,2015.
- Patent WO 2014016003 A1: Use of biotin for the treatment of multiple sclerosis.
http://www.google.com/patents/WO2014016003A1?cl=en. Accessed on January 28, 2015.
- 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;16:1325-1327.
- Watzlawik JO, Warrington AE, Rodriguez M. PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLoS One. 2013;8:e55149.