review

Bioengineered 4:3, 140–146; May/June 2013; © 2013 Landes Bioscience

The development of myelin repair agents

for treatment of multiple sclerosis
Progress and challenges
Robert P. Murphy,1 Keith J. Murphy1,* and Mark Pickering1,2
Neurotherapeutics Research Group; UCD School of Biomolecular and Biomedical Science; UCD Conway Institute; University College Dublin; Dublin, Ireland; 2UCD School of
1

Medicine and Medical Science; University College Dublin; Dublin, Ireland

©2013 Landes Bioscience. Do not distribute

Keywords: myelin, multiple sclerosis, remyelination, oligodendrocyte, neurodegeneration

Abbreviations: MS, multiple sclerosis; CNS, central nervous system; BBB, blood brain barrier; IFNβ, interferon beta; OL,
oligodendrocyte; OPC, oligodendrocyte precursor cell; SVZ, subventricular zone; RXR, retinoid X receptor; EAE, experimental
autoimmune encephalomyelitis; LINGO-1, leucine rich repeating and Ig containing NOGO receptor interacting protein-1; LPC,
lysolecithin; ARR, annualized relapse rate; EDSS, expanded disability status scale

Demyelination results in interrupted axonal signal conduc-

Multiple sclerosis (MS) is an inflammatory demyelinating
tion as well as secondary axonal degradation which manifests as
disorder which affects the central nervous system.
Multiple sclerosis treatment has traditionally focused on
a combination of any or all of the following symptoms: blurred
preventing inflammatory damage to the myelin sheath. vision, muscle stiffness, muscle weakness, tremor, fatigue, ver-
Indeed, all currently available disease modifying agents tigo and cognition impairment. Based on the pattern of symptom
are immunomodulators. However, the limitations of this appearance, MS can be classed as one of either relapsing remit-
approach are becoming increasingly clear, leading to the ting MS or progressive MS. The most common form of MS,
exploration of other potential therapeutic strategies. In relapsing remitting MS, is characterized by acute inflammatory
particular, targeting the endogenous remyelination system attacks associated with bouts of disability, separated by periods of
to promote replacement of the lost myelin sheath has shown remission where no symptoms are apparent. However, this often
much promise. As our understanding of remyelination biology develops into secondary progressive MS which is characterized by
advances, the realization of a remyelinating therapeutic worsening disability accompanied by a shortened or absent remis-
comes closer to fruition. In our review, we aim to summarize
sion phase. Primary progressive MS, in which there is progressive
the limitations of the current immune focused treatment
strategy and discuss the potential of remyelination as a new
clinical deterioration from the onset of the disease, can also occur
treatment method. Finally, we aim to highlight the challenges but is less common. To date, MS therapeutics have only been suc-
in the identification and development of such therapeutics. cessful in reducing the relapse rate in relapsing remitting forms
of MS. No disease modifying agents which effectively halt the
progressive forms of MS have been identified. In the following
sections we aim to summarize the current immunomodulating
Introductory Comments therapies available, the search for new remyelinating MS thera-
peutics and some of the potential challenges in identifying and
Multiple sclerosis is an autoimmune disease distinguished by the assessing such therapeutics.
primary pathological hallmarks of central nervous system (CNS)
demyelinated lesions associated with inflammatory infiltrates. Current Therapies
The prevalence of MS varies greatly worldwide but is estimated
to affect between 2 and 150 per 100,000 people,1 depending on The current therapeutic strategy for MS is aimed at preventing
the country or specific population, making it one of the most inflammatory damage to the CNS through the use of immuno-
common disabling disorders. The white matter lesions associ- modulating drugs. Interferon β (IFNβ), glatiramer acetate, natal-
ated with MS are classically described as resulting from myelin- izumab and Fingolimid are the leading therapies currently used in
reactive lymphocytes crossing the blood brain barrier (BBB) and the management of MS symptoms. Fingolimid, the most recently
entering the brain and spinal cord. Once in the CNS these cells approved of these, is a sphingosine analog which interacts with
drive an immune response which damages oligodendrocytes, the sphingosine 1-phosphate receptors on lymphocytes to reduce auto-
cells responsible for the production of myelin, and strips axons of reactive cell infiltration into the CNS.3,4 IFNβ has been shown to
the myelin sheath.2 have inhibitory effects on the proliferation of leukocytes, antigen
presentation and T-cell migration across the blood-brain barrier,4,5
*Correspondence to: Keith J. Murphy; Email: [email protected] but it is only partially effective at delaying disease progression.6
Submitted: 09/28/12; Revised: 11/08/12; Accepted: 11/09/12 Glatiramer acetate is a synthetic polymer originally designed to be
http://dx.doi.org/10.4161/bioe.22835

140 Bioengineered Volume 4 Issue 3

 review REVIEW

an analog of myelin basic protein, a myelin component, and thus It has been hypothesized that impaired OPC differentiation,
act as a decoy for scavenging immune cells. It now appears that its rather than migration or proliferation is the primary underlying
mechanism of action lies in its ability to shift a pro-inflammatory cause of the reduced remyelination competence seen in MS.20
Th1 cytokine profile to an anti-inflammatory Th2 cytokine pro- Pathological evidence from human post mortem tissue appears
file.7 Natalizumab is a humanized monoclonal antibody directed to support this hypothesis. It has been shown that MS lesions are
against the alpha4 subunit of the integrin VLA4 antibody block- populated with OPCs21,22 but that these cells lose the ability to
ade of which helps to limit leukocyte adhesion and transmigration differentiate into mature oligodendrocytes.23 Unsurprising then
across the blood brain barrier.8 are findings which show that the white matter lesion microenvi-
However, natalizumab treatment increases the risk of JC virus ronment contains factors which inhibit OPC differentiation.24,25
infection leading to progressive multifocal leukoencephalopathy, Based on this evidence, much energy has been focused on ways
another demyelinating disorder, developing in some patients.9,10 to overcome OPC differentiation failure and spark endogenous

©2013 Landes Bioscience. Do not distribute

As a result of this, the use of natalizumab is now restricted. remyelination.
By dampening the immune response, these disease modifying Encouragingly, multiple influential pathways or signals have
agents have proven to be effective at reducing the relapse rate of now been discovered which regulate OPC differentiation. Wnt,
MS. However, they do not effectively halt the progressive clinical Notch and retinoid X receptor (RXR) signaling have all been
neurological decline seen in MS most likely because they lack a shown to be regulators of OPC differentiation and to play an
direct action on CNS axons and myelin. This has resulted in the important role in myelinogenesis and/or remyelination. These
situation where the current therapies are moderately effective for pathways are particularly interesting as they have already been
patients with relapsing remitting MS, but treatments are of little extensively studied in other settings, and there are pharmaco-
benefit in progressive forms of MS.11 logical tools available to manipulate these pathways. Promisingly,
some of these pharmacological tools have already been used to
A Paradigm Shift for MS Therapeutics: demonstrate proof of principle that these pathways are valid ther-
Promoting Myelin Repair apeutic targets for demyelinating disorders. Activation of RXR
with the agonist 9-cis-retonic acid has been shown to enhance
Promoting the repair of the white matter damage, rather than remyelination in vivo and in vitro,26 inhibition of WNT signal-
solely trying to prevent it from occurring, would theoretically be ing through GSK-3β antagonism stimulate OPC differentia-
beneficial in both relapsing and progressive forms of MS. This tion and remyelination in vivo,27 and Notch inhibition has been
represents a new therapeutic strategy which could restore func- shown to alleviate experimental autoimmune encephalomyelitis
tional deficits to normal and prevent progressive decline. However (EAE),28 an animal model of MS. Given that these pathways are
there is currently no disease modifying agent which can be said also areas of interest for anti-cancer therapeutics,29-32 there may
to do this. In order to fill this treatment gap there has been a be a concerted effort to quickly develop and test drugs which
focus in basic research to identify signals, pathways and phar- target these pathways in the context of MS.
macological targets to enhance endogenous repair. Interestingly, Perhaps the most important of these recently identified OPC
there are hints that both glatiramer acetate and fingolimid inter- differentiator regulators is leucine rich repeating and Ig domain
vention may also have a reparative effect,12,13 but this appears to containing NOGO receptor interacting protein-1 (LINGO-1).
be a by-product of their immunological effects rather than result- LINGO-1 was first identified as a CNS specific transmembrane
ing from a targeted effort to enhance remyelination. protein which interacts with the Nogo-66 receptor complex 33 that
Remyelination, the regeneration of the myelin sheath, occurs acts as a strong inhibitor of axonal sprouting.33,34 More recently,
spontaneously throughout the course of MS. Typically, the new LINGO-1 has been shown to negatively affect myelination35 and
myelin sheath is thinner and shorter than non-injured myelin14 to inhibit OPC differentiation.36 LINGO antagonism has been
but is still functional; in so far as acting to return axonal con- shown to enhance remyelination in EAE as well as ameliorat-
duction to normal levels.15 Of additional benefit, remyelination ing the paralytic symptoms seen in this model.37 Importantly
appears to have neuroprotective properties, preventing the sec- LINGO-1 antagonism has also been shown to promote CNS
ondary axonal damage seen in MS.16 For unknown reasons, remyelination in two toxin induced models of demyelination,
remyelination ultimately fails in MS leading to the loss of chroni- and it appears that this is achieved through direct regulation of
cally demyelinated axons and the progressive neurological deficits OPC differentiation.38
seen. This encouraging data has led to a LINGO 1 antagonist
The remyelination process requires the generation of new (BIIB033) entering clinical trials for MS. The outcome of these
mature oligodendrocytes (OLs) from oligodendrocyte precursor trials will be a watershed moment for remyelinating therapeutics
cells (OPCs) that must be recruited to the demyelinated lesions.17 as it will offer proof of concept that an agent which promotes
OPCs, which are capable of responding to injury and regenerat- remyelination is beneficial in MS. Should LINGO-1 antagonism
ing the myelin sheath, are plentiful in the CNS,18,19 but correct be shown to have marked benefit clinically, it will become the
coordination of oligodendroglial precursor migration, prolifera- prototypical “remyelinating agent.” Other potential therapies
tion and differentiation is required for remyelination to success- are thus likely to follow the same path of pre-clinical develop-
fully occur. A failure in any one of these processes would impair ment, and to be evaluated on the same criteria that LINGO-1
or even prevent remyelination occurring. antagonism has been shown to meet. A LINGO-1 antagonist was

www.landesbioscience.com Bioengineered 141

brought to the clinic on the back of robust effects in animal mod- required as it is not sufficient to rely on the degree of functional
els of demyelination. However, it must be noted that at this stage, recovery of symptoms as indicative of remyelination. Extra dili-
it is completely unknown whether these models can act as reliable gence is needed to ensure that a therapy which ameliorates EAE
predicators of clinical efficacy. is truly enhancing remyelination and not just simply acting to
influence the onset of EAE. This becomes even more important
Challenges of Identification and Development when it is taken into consideration that drug interventions are
of Remyelinating Therapeutics often given before EAE symptoms develop.37,53 Even extensive
histological analysis may not be enough to conclusively confirm
Preclinical testing of MS therapeutics has historically relied on a remyelinating effect as it can be difficult to assess the extent of
models which approximate the immunological component of demyelination and remyelination independent of the impact of
MS. However, models of demyelination which are independent axonal loss and inflammatory infiltrates. Perhaps most worrying

©2013 Landes Bioscience. Do not distribute

of inflammation have increased in popularity as the search for however, is the notoriety that EAE is gaining as a poor predic-
remyelinating therapeutics intensifies. None of these models are tor of clinical efficacy.54 Many interventions have been shown to
without weaknesses and one should be aware of the limitations of ameliorate symptoms in this model, but few have been successful
these models for assessing remyelinating therapeutics. clinically, raising concerns over this model’s suitability for thera-
The classic model for identifying and assessing MS therapeu- peutic assessment.
tics has been EAE. Initially described in the 1930s in primates,39 Unlike EAE, which aims to approximate the pathophysiol-
EAE was later adapted for rodents to facilitate MS research. ogy of MS, toxin induced demyelination is used to study demy-
Classically EAE is described as CD4+ Th1 cell response against elination and remyelination in isolation of an inflammatory
myelin,40 which is typically induced by teaming one of the myelin environment. Therefore, the interpretation and analysis of a
components, MBP, MOG or PLP, with an adjuvant to induce an remyelinating effect should be more straightforward than with
auto-aggressive response against myelin. Less frequently EAE is EAE. Several toxins have been shown to induce CNS demyelin-
induced by adoptive transfer of CD4+ 41,42 myelin reactive cells to ation, including but not restricted to, ethidium bromide, lyso-
a naïve animal. Typically EAE manifests as a distinct hindlimb lecithin and cuprizone. Of these three, the two most extensively
paralysis accompanied by white matter lesions with inflamma- studied models, and the two models in which LINGO-1 antago-
tory cell infiltrates. This model is extremely flexible and by vary- nism has proven to be effective, are cuprizone diet-induced demy-
ing the myelin component or animal strain, relapsing remitting, elination and lysolecithin-induced focal demyelination.
chronic progressive or acute forms of EAE can be induced.43 Lysolecithin (LPC) is a known potent demyelinating agent
Studies using this model have shown that by dampening the which is long established as causing demyelinated focal lesions
immune response or modulating the infiltration of white cells upon injection into the spinal cord.55 Since then LPC has been
into the CNS, the severity of EAE can be reduced.44 Indeed, shown to cause demyelination in other central nervous system
fingolimid, glatiramer acetate, IFN-β and natalizumab have all regions56 as well as exhibiting demyelinating properties when
been shown to have efficacy in some model of EAE.44-48 For years, applied to the peripheral nervous system.57,58 In the context of
EAE has proven to be the basis for the greater understanding of CNS remyelination, LPC-induced spinal cord lesions still appear
the immunological component of MS as well as becoming the be the model of choice as the unidirectional path of axons in the
standard test for identifying immunomodulating MS therapies. spinal cord makes it easy to assess myelination and axon numbers
The question remains, however, as to whether EAE holds by microscopy. Upon LPC injection, measurable demyelination
much value in investigating remyelination therapeutics. One can be seen within hours.55 Remyelination occurs over the fol-
of the EAE model’s greatest strengths lies in its flexibility and lowing weeks,56 with the rate of recovery depending on the age of
reproducibility across multiple species. The variances in species the animals.59 There appears to be relatively little axonal loss in
and auto-antigens used to study EAE result in differences in the this model,55 with LPC appearing to function by acting primar-
pathology of EAE, meaning that one must carefully choose the ily on oligodendrocytes at the concentrations typically used in
correct model to avoid misleading or uninformative results. For these studies. Although oligodendrocytes have been shown to be
example, it is known that MBP induced EAE in Lewis rats has a particularly sensitive to LPC toxin,60 it is uncertain why this is
large inflammatory component but CNS demyelination is absent the case. This model provides a platform for the study of inherent
or highly restricted,49 making this model unsuitable for investi- remyelination ability, as well as providing a window of oppor-
gating remyelinating therapeutics. It is now known that all forms tunity for assessment of treatments which accelerate the repair
of rodent EAE result in inflammatory infiltrates into the CNS process.
but only some versions reproduce significant demyelination.50 More recently LPC has been applied to in vitro organotypic or
In particular, remyelination in MOG induced EAE in C57B6 multicellular systems,61-63 where it reproduces the cycle of demy-
mice is frequently studied, but the suitability of this model for elination and remyelination seen in vivo. In particular, organo-
assessing a purely remyelinating therapeutic still remains ques- typic-based models are becoming a popular research tool as a first
tionable. The paralytic symptoms seen in this form of EAE are pass system to identify potential remyelinating therapeutics before
likely due to a mixture of edema, loss of axonal integrity and progressing to expensive and laborious in vivo studies. Jarjour
demyelination rather than resulting exclusively from persistent et al.64 present a comprehensive review of these in vitro demyelin-
demyelination.51,52 Careful interpretation of results is therefore ation models, some of which use LPC as demyelinating toxin.

142 Bioengineered Volume 4 Issue 3

 Cuprizone-induced demyelination is rapidly becoming the functional deficit rescue by a therapy may also increase the
standard model for studying remyelination biology. A powdered probability of therapy efficacy translating from animal model
cuprizone diet of 0.2% w/w over a 6–8 week period produces a to clinical trial. Return of normal signal transmission indicates
reliable myelin insult in several different brain regions, notably that the myelin sheath has not only been restored but also that
the hippocampus,65,66 the cortex67-69 and the corpus callosum.70,71 the underlying axons have been returned to functional norms
The corpus callosum is the most studied of these regions, pri- and that remyelination has indeed acted as a neuroprotectant.
marily because it is a large white matter tract which is easy to Interestingly, it has already been shown that axon conduction is
identify and to assess levels of myelin. Although first described impaired in cuprizone demyelination,80 reaffirming its suitability
in the 1960s,72 the exact mechanism of cuprizone demyelination as demyelination model. However, conduction does not return
is unclear. Copper chelation,73 mitochondrial dysfunction74 and to normal levels even after what would be considered complete
inhibition of OPC differentiation75 have all been suggested to remyelination80,81 as measured by the typical histological mark-

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play a role. Whatever the cause of demyelination, upon removal ers thus, further investigation is required. These finding also
of cuprizone from the diet, remyelination spontaneously occurs suggest that restoration of the myelin sheath in the cuprizone
over a period of weeks.76 Similar to LPC-induced demyelination, model occurs subsequent to significant axonal damage and remy-
this model has provided a platform for basic remyelination biol- elination alone is not sufficient to reverse functional deficits. In
ogy as well as the assessment of interventions which may acceler- contrast, LPC demyelination has been shown to cause conduc-
ate the spontaneous repair process. tion block, which is restores to normal upon remyelination.82 It
Although the toxin-induced models of demyelination have should be noted that LINGO-1 antagonism has been shown to
offered valuable insights into the basic biology of remyelination, have functional benefits as measured by conduction velocity,38
there are some caveats which may cast doubts over their ability to bolstering the hopes that it will display clinical efficacy, although
act as an indicator of clinical efficacy. this property appears to have been largely undervalued in com-
First, any positive remyelinating effects recorded are in iso- parison to data gathered from histological analysis.
lation of an inflammatory environment. Inflammation, at the The models currently available are imperfect. EAE models
very least, has a role to play in the pathophysiology of MS. Any approximate the immunological components of MS but they
pro-myelin therapy will have to overcome an inflammatory envi- may not be appropriate for assessing remyelinating therapeutics.
ronment to be of clinical efficacy. Before being confident of an On the surface, targeted testing of remyelinating therapeutics in
agent’s clinical relevance one has to balance the knowledge that toxin induced demyelination appears to be more rational strat-
toxin models have minimal inflammation, while the standard egy, but it is undetermined if these models can act as good pre-
inflammatory model used for MS therapeutics is likely to be dictors of clinical efficacy. However, the value of these models in
unsuitable for identifying remyelinating agents. Therefore effi- providing insight into the biology of myelination processes, and
cacy in either one, or both, of these models, does not necessarily identifying promising therapeutic leads should not be invalidated
guarantee clinical relevance of an agent. because of this uncertainty.
Second, neither toxin-induced model has a true functional BIIB033 is the first remyelinating therapeutic to enter clini-
readout of demyelination or remyelination. The ultimate aim of cal trials, largely based on its successes in the aforementioned
a remyelinating therapeutic is to reverse or at least halt the func- preclinical models. In the coming years it is hoped that several
tional deficits seen in MS. In order to achieve this, saltatory con- other drugs will join BIIB033 at this stage of development. The
duction must be restored in freshly remyelinated axons, yet CNS judgment of efficacy of a remyelinating therapeutic may prove to
function is rarely studied in these models. Unlike EAE there are be less straightforward than that of an immunomodulator as MS
no gross behavioral changes which can be easily assessed. There symptoms can result from a mixture of axonal loss, demyelination
have been some subtle changes noted in the behavior of cupr- and inflammation. Post mortem tissue is not readily available for
izone-treated mice, including prepulse inhibition deficit77 and study, biopsies are difficult to obtain and it is unknown how or if
changes to motor coordination,78,79 but it needs to be fully elu- remyelination will correlate with MS symptoms. Imaging tech-
cidated if these deficits are directly and exclusively the result of niques which visualize the extent of remyelination could offer the
demyelination. solution to this problem. Progress is being made in this area,83,84
Typically the success of a remyelinating therapeutic in vivo is but we are still some time away from reliably monitoring remy-
defined by assessment of myelin in post mortem tissue through elination clinically.
the use of electron microscopy, classic histological stains such How then, can the impact of a remyelination therapeutic be
as luxol fast blue or immunofluorescent staining against myelin measured if we cannot easily quantify remyelination directly and
components. While these tools can demonstrate that myelin are uncertain to what degree efficacy will correlate with symp-
sheath has been restored, there is an underlying assumption that toms? One possible solution is to assess new remyelinating agents
the ensheathed axons are once again functional. In truth, these in combination with existing immunological treatments. The
histological assessments reveal little of the integrity or functional- current disease modifying agents are known to reduce the fre-
ity of the axons ensheathed underneath. quency of relapses, as measured by the annualized relapse rate
Restoration of CNS conduction velocities, combined with (ARR). As relapses are linked to an immune response, a remye-
histological confirmation of myelin, would constitute compelling lination therapeutic, with a mechanism independent of immuno-
evidence of the benefit of a remyelinating agent. Demonstrable modulation, is unlikely to affect the ARR score. A second scoring

www.landesbioscience.com Bioengineered 143

system, the expanded disability status scale (EDSS), is used to an immunomodulator alone, any halt or reversal in neurological
quantify disability in MS. Increasing EDSS scores, indicative of deterioration as measured by the EDSS score would most likely
worsening disability, are typically seen over the course of MS, be attributable to the remyelinating agent.
particularly in the progressive phases. It is known that the current In conclusion, there is large scale on-going research activity
MS treatments have minimal impact on this parameter, likely focusing on the development of remyelinating therapeutics. There
because disability largely results from the loss of chronically are now several established models which are useful for studying
demyelinated axons, rather than primary inflammation. A remy- remyelination biology which have helped identify multiple drug
elinating therapeutic, which theoretically repairs the damage targets, but, at this stage, it is simply unknown if efficacy in these
caused by inflammation and prevents secondary axonal loss from established models will translate into tangible clinical benefits.
this damage, should therefore reduce the EDSS score. Whether It is only now, with the first targeted remyelinating therapeutic
a remyelinating therapeutic alone would be powerful enough to entering clinical trials that we will begin to learn what refine-

©2013 Landes Bioscience. Do not distribute

overcome the inflammatory damage in MS and reduce the EDSS ments of these models are needed to improve successful crossover
score is unknown. This raises the possibility of a two pronged from pre-clinical to clinical stage. Moreover, it needs to be taken
treatment strategy: combining a remyelinating agent with an into account that the previously used methodology for assessing
immunomodulator. This would at least reduce the confound- immunomodulating MS therapeutics may not be applicable for
ing factor of inflammation, while allowing for assessment of any the determination efficacy in the context of remyelinating agents.
synergistic effects. The already established EDSS scoring system
could, perhaps, act as a proxy to measure the impact of the remy- Disclosure of Potential Conflicts of Interest
elinating agent. As functional improvements are not seen with No potential conflicts of interest were disclosed.
10. Clifford DB, De Luca A, Simpson DM, Arendt G, 20. Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J,
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