MultipleSclerosis (MS) is an autoimmune disease affecting the central nervous system(CNS).It is characterized by autoreactive immune cells that induce demyelination andneuronal degradation(1). There are three subtypes of MS based ondisease progression: relapsing-remitting MS (RRMS), secondary progressive MS(SPMS), primary progressive MS (PPMS)(2). Current drug therapies,which target the autoimmune aspect, have shown efficacy for RRMS but havefailed to help SPMS and PPMS(2-3).
These autoimmune based therapiescan help prevent and slow down neural damage but cannot repair the lost myelin(4).Re-myelination of neurons is the only way to restore the function that has beenlost and research to find therapies are currently underway(5). When neurons in the CNS are injuredor damaged oligodendrocyte progenitor cells (OPCs), the myelin-producing cellsof the CNS, respond to the area. These cells would then mature anddifferentiate into adult oligodendrocytes(2,5). In MS patients,these OPCs are blocked from differentiating by changes in the local environmentsuch as extracellular matrix components brought in through vasculature leakage(5).Myelination of axons enables fast, salutatory impulse propagation(4).The myelin sheath creates a low capacitance environment allowing for increasedspeed, decreased refractory periods, and more action potentials per unit oftime(6-7).
Demyelinated axons can lead to motor, cognitive andsensory impairments such as blurred vision, difficulty in controllingmovements, difficulty controlling bodily functions(2,4,7). If theneural cell remains demyelinated it will try to overcome the short circuitrywhich will lead to oxidative injury, energy failure, possible axonal injury,glial scars and ultimately neuronal death(8-9). The continuation ofdemyelination forms lesions and will cause brain atrophy, these can be markersfor the progression of MS in patients. Current treatments for MS are basedon reducing inflammation and autoreactive immune attacks. These treatments aresuccessful at reducing the severity and frequency of relapses/attacks(5).While multiple disease-modifying therapies have been approved for use inpatients with RRMS there is only one FDA approved therapy for patients withPPMS, ocrelizumab(10). Although there are no current therapies fordirect re-myelination, some current therapies may be able to be used incombination with future re-myelinating therapies. Mitoxantrone, an FDA approvedimmunosuppressive therapy, has been shown to reduce axonal damage in severepatients(3).
Immunosuppressive drugs like mitoxantrone can reduceneuronal degeneration and improve neuronal survival, which allows more time foreither natural based re-myelination or in the future for new therapies incombination to help re-myelinate neural cells(5). Since the local environment oflesions is not conducive for OPC differentiate, stem cell transplantationtherapy is a viable option for further research. Donor neural precursor cellswere injected into mice and found in areas of damage, undergoingre-myelination. The neural precursor cells also release platelet-derived growthfactor-AA and fibroblast growth factor-2 which can help signal endogenous OPCsto proliferate and differentiate into mature oligodendrocytes which can alsohelp re-myelinate damaged neurons(2).
Mesenchymal stem cells (MSCs)are another potential stem cell therapy. MSCs were injected into mice and foundable to cross the blood-brain barrier and migrate to sites of demyelination.MSCs have shown major improvement in re-myelination in mice but because theyare stem cells they pose a risk of differentiating into multiple cell types.
Toavoid unwanted differentiation MSCs can be cultured in a neural progenitormedium to create MSC-derived neural progenitors (M-NPs). When further researchwas done to test the efficacy of M-NPs, researchers found that there was lessdemyelination in the spinal cord, there was increased motor function and thatM-NPs express anti-T-cell properties because there was a lower concentration ofT-cells. With these results, the FDA approved Phase I clinical trials of M-NPsbeing injected intrathecally into the cerebral spinal fluid(2,5). Anotherform of stem cell therapy is hematopoietic stem cell transplantation.
Thetransplantation is following a high-dose immunosuppressive therapy, thisprocedure in Phase II trials has sustained remission of active RRMS and shownsigns of regeneration. The combined therapy works by resetting the immunesystem to self-antigens and eradicating autoreactive cells(9). Antibodies which are part of theautoreactive system that is targeting neurons and causing MS are another typeof therapy that is being explored. The Nogo-A co-receptor LINGO-1 is atransmembrane protein expressed in neurons and oligodendrocytes where it is anegative regulator of oligodendrocyte differentiation and consequently inhibitsmyelination(2,5,8). Blocking this receptor would be a potentialtherapeutic strategy for inducing OPC differentiation and re-myelination. Theanimal model used to test these effects is called experimental autoimmuneencephalomyelitis (EAE), which is induced through injections(2).
Throughsuccessful trials of anti-LINGO-1 antibodies in mice induced with EAE, axonsincreased their integrity and myelin sheaths began to form resulting in overallaxonal recovery(2,9). With success in animal models the antibodyBIIB033, which is an IgG1 monoclonal antibody, was created(2,5,8-9).In Phase I trials in patients showed it was well tolerated and was unexpectedlyable to cross the blood-brain barrier through detectable concentrations in thecerebral spinal fluid(2,8). The first Phase II trial was conductedin patients with a first episode of optic neuritis, and after 24 weeks fasterimpulse conduction was recorded along the optic nerve compared to the placebogroup, which shows myelin repair(5,8-9).
A different Phase II trialinvestigating the impact of disease progression in patients with RRMS and SSMSwas conducted(5,8-9). Another antibody, rHIgM22, which binds tomyelin and the surface of oligodendrocytes and prevents their death throughapoptosis is another possible therapy for patients with MS(2,5,8-9).rHIgM22 was first tested as a treatment for Theiler’s murine encephalomyelitisvirus (TMEV) model of MS in mice(2).
Although this antibody binds toOPCs it is shown to inhibit differentiation and it is unknown how it stillpromotes myelin repair(5). Treatment of rHIgM22 in TMEV model miceshowed a 64% decreased in lesion size compared to the control group(2).The efficacy of this treatment was tested in Phase I clinical trials and withsuccess in the initial single dose therapy a second Phase I trial is underwaytesting dose escalation(2,5,8). Another study that shows a potentialtherapy for MS is the use of high-dose biotin. Biotin is a water-solublevitamin, part of the B-complex family that acts as a cofactor for decarboxylaseenzymes(8-9). Biotin is a cofactor for two isoforms of acetyl-CoAcarboxylase (ACC1 and ACC2), ACC1 is a catalyst in the rate-limiting step inthe synthesis of fatty acids detectable in myelin(8).
Through itsrole in ACC1 biotin may possible treatment for promoting re-myelination byincreasing the fundamental building blocks needed for myelin sheath production(8).In an open-label pilot study of biotin (100-300 mg/day) revealed improvement indisease progression in patients with SPMS and PPMS that have optic neuropathyand spinal cord injuries(8-9). The efficacy observed in thisopen-label pilot study shows biotin is effective at reducing chronic disabilityand in reversing disease progression(8). MD1003 is an oral form ofhigh-dose pharmaceutical-grade biotin in development for the treatment of PPMS(8).A Phase III trial of a 300 mg daily dose of biotin is currently testing theefficacy and safety of such a high dose(8).
The results from bothstudies showed that there was a delay in the time between the start oftreatment and the start of clinical improvement in patients. This may suggestthat biotin acts in some slow repair mechanism but currently does not provideenough evidence for clinical treatment. There is more data to be collected fromthe studies that may change the assessment of the drug viability(8). One of the oldest anti-psychoticdrugs, lithium, is a potential therapy route to promote OPC differentiation,proliferation, and increased myelin(9,11). Lithium is an inhibitorof glycogen synthase kinase-3 (GSK-3), a serine-threonine protein kinase and alsohas anti-inflammatory properties(9,11). Currently, lithium is usedto treat bipolar and depressive disorders, and there is growing evidence thatit exhibits neuroprotective and neurogenesis factors(11). Theinhibition of GSK-3 mimics the Wnt/beta-catenin signaling pathway, which is adriver of myelin gene expression(11). In one study lithium chloride(LiCl) was used to study the effect of re-myelination after myelin injuries(11).
LiCl was able to increase gene expression of myelin genes and decrease the g-ratio,which is defined as the diameter of the axon divided by the diameter of theaxon plus myelin(2,11). One limitation of re-myelination is thatre-myelinated axons tend to have thinner myelin sheaths which means decreasedconduction of impulse signals(2). A lower g-ratio shows that theaxon has a thicker myelin sheath and is better for nerve cell function(2).Although this study was testing the re-myelination of a peripheral facialnerve, the researchers of the study believe that this information and strategycan be applicable to the CNS and a possible treatment for MS(11). Aseparate Phase I/II trial of progressive MS forms is currently underway(9).Although this study is based on the idea of lithium as a regulator ofinflammation, disease severity will be measured and possible re-myelinationcould be a potential outcome. Pregnancy, a possible reducing agentof disease activity in MS. Domperidone is a dopamine-2 receptor antagonist,which can increase secretion of prolactin(9).
Studies performed inEAE models showed that prolactin can promote myelin repair and therefore is apotential target for re-myelination therapy in patient with MS(9).There is well-established data to show the disease reducing activity in MS thatoccurs during pregnancy, likely due to the higher levels of prolactin secretion(9).There is currently a Phase II trial of domperidone underway for patients withSPMS(9). Although current treatments forre-myelination in patients with multiple sclerosis are absent there is greatpotential for current research to solve this problem.
There are many differentmechanisms by which therapies directed towards re-myelination can explore. Usingthe body’s own re-myelination processes like stem cell and antibody therapiesis a current route of research. Also by discovering the pathways involved inre-myelination and using drugs to target different steps like lithium chloride,is another viable route in finding therapies for MS. Re-myelination therapiesalone will not be the most suitable form of treatment, in combination theyshould also include anti-inflammatory and neuroprotective aspects as well. Byreducing the damage done by inflammation and the bodies self-reactive immunecells is important alongside with neuroprotective factors to maintain neuralintegrity as long as possible(1,5).
This allows a greater window forre-myelination and recovery from the symptoms of MS. Multiple sclerosis is acomplex, multifactorial disease that with future therapies is showing muchpromise in the efficacy of treatments and hopefully one day a cure.