REviEwS

Progressive multiple sclerosis:

from pathophysiology to therapeutic
strategies
Simon Faissner   1,2*, Jason R. Plemel   3, Ralf Gold1 and V. Wee Yong   2*
Abstract | Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system
that involves demyelination and axonal degeneration. Although substantial progress has been
made in drug development for relapsing–remitting MS, treatment of the progressive forms of
the disease, which are characterized clinically by the accumulation of disability in the absence
of relapses, remains unsatisfactory. This unmet clinical need is related to the complexity of the
pathophysiological mechanisms involved in MS progression. Chronic inflammation, which occurs
behind a closed blood–brain barrier with activation of microglia and continued involvement
of T cells and B cells, is a hallmark pathophysiological feature. Inflammation can enhance
mitochondrial damage in neurons, which, consequently, develop an energy deficit, further
reducing axonal health. The growth-inhibitory and inflammatory environment of lesions also
impairs remyelination, a repair process that might protect axons from degeneration. Moreover,
neurodegeneration is accelerated by the altered expression of ion channels on denuded axons.
In this Review, we discuss the current understanding of these disease mechanisms and
highlight emerging therapeutic strategies based on these insights, including those targeting the
neuroinflammatory and degenerative aspects as well as remyelination-promoting approaches.

1
Department of Neurology,
St. Josef-Hospital,
Ruhr-University Bochum,
Bochum, Germany.
2
Hotchkiss Brain Institute
and Department of Clinical
Neurosciences, University
of Calgary, Calgary, Alberta,
Canada.
3
Department of Medicine,
University of Alberta,
Edmonton, Alberta, Canada.
*e-mail: simon.faissner@
rub.de; vyong@ucalgary.ca
https://doi.org/10.1038/
s41573-019-0035-2
Multiple sclerosis (MS) is a chronic inflammatory condi­
tion of the central nervous system (CNS) that is charac­
terized by demyelination with concomitant axonal and
neuronal degeneration1. Approximately 85% of patients
with MS present with a relapsing–remitting course of the
disease (RRMS), and the majority of these, as shown in
natural history studies, advance to a progressive disease
course — termed secondary progressive MS (SPMS) —
after 15–20 years of disease manifestation2. The remain­
ing ~10–15% of patients have a slow and continuous
neurological deterioration without definable relapses, a
type known as primary progressive MS (PPMS). Despite
tremendous successes in the development of therapies
for RRMS3 and disease-modifying therapies that delay
the conversion to SPMS4, progressive MS has limited
treatment options. Indeed, medications that are highly
effective in RRMS have failed in the treatment of progres­
sive MS, as exemplified by the sphingosine-1-phosphate
receptor (S1PR) modulator fingolimod, which did not
reduce the risk of disability progression in patients
with PPMS in the phase III INFORMS trial5. However,
modest advances have been made in progressive MS
with two positive phase III clinical trials showing a
reduc­tion in confirmed disability progression of approxi­
mately 21–24%. Indeed, the phase III ORATORIO trial in
PPMS6 led to approval of the anti-CD20 antibody ocre­
lizumab as the first therapy in this setting. Moreover,
in March 2019, the US Food and Drug Administration
(FDA) approved the S1PR modulator siponimod for the
treatment of SPMS in patients with active disease on
the basis of findings from the phase III EXPAND study7.
The reason why treatment of progressive MS remains
elusive is multifaceted. A major explanation is that degen­
erative mechanisms that characterize progressive MS
are distinct from the largely inflammatory mechanisms
that give rise to relapses in RRMS, and that the neuro­
degenerative processes are not sufficiently targeted by the
approved immunomodulatory compounds (for example,
siponimod and ocrelizumab). In addition, uncertainty
regarding the pathophysiological mechanisms involved
in progressive MS, an understanding that has been lim­
ited by a paucity of relevant preclinical animal models,
challenges the clinical translation of new treatments
(Box 1). Our current understanding is that progressive
MS is characterized by chronic inflammation behind a
closed blood–brain barrier with activation of microglia
and continued involvement of T cells and B cells. Release
of reactive oxygen species (ROS) and nitrogen species
(RNS) contributes to mitochondrial and axonal damage,
which, ultimately, leads to neurodegeneration.

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Box 1 | controversies in progressive Ms pathophysiology
Developing new therapeutic agents with precise modes of action requires an
understanding of pathological mechanisms. However, many controversies exist
regarding the pathophysiology of progressive multiple sclerosis (Ms). For example,
progressive Ms is characterized by neurodegeneration, yet whether early
neurodegeneration drives autoimmune injury, or whether ongoing inflammation
reaches a threshold to trigger neurodegeneration, is still unclear179. another unclear
point is whether neurodegeneration is independent of or dependent on chronic
inflammation. still, the notion that neurodegenerative and inflammatory injury
mechanisms interact to drive disability progression is widely agreed upon. without
a clear understanding of the pathological mechanisms that drive progressive Ms,
the in vivo modelling of the disease in animals is challenging.
animal models that have been useful in the development of therapies for relapsing–
remitting Ms (rrMs), such as experimental autoimmune encephalomyelitis (eae),
have been largely unsuccessful in the identification of therapies that slow Ms
progression. Models that have been championed for progressive Ms, such as the
non-obese diabetic (NOD) mouse model or the Biozzi antibody high (aBH) mouse
model of eae (a proposed model of progression), have autoimmune injury and
secondary progression of disability, but these models assume that inflammation drives
progression, which is debatable. Non-autoimmune models, such as the mouse model
of cuprizone-induced demyelination, have white matter degeneration, but the extent
to which this approach models progressive Ms is unclear. a 2019 study showed that
intravenous injection of β-synuclein-reactive T cells induces grey matter demyelination
and neurodegeneration in Lewis rats, which could be a new model to study cortical
degeneration180. Nevertheless, preclinical models that mimic pathological aspects of
progression as well as valid and reliable paraclinical markers are lacking.
the value of testing and clinically translating new medications for progressive
MS developed in these preclinical models is unclear, as has been illustrated by
several negative trials, including those investigating fingolimod (INFORMS)5,
natalizumab (asCeND)19 and rituximab (OLYMPus)45. the poor understanding of the
pathological mechanisms in progressive Ms makes it challenging to tailor targeted
therapeutic agents.
In this Review, we discuss the current understanding
of the pathophysiology of progressive MS and highlight
promising treatment approaches as well as auspicious
preclinical and clinical studies. Owing to the controv­
ersies regarding the pathophysiology of progressive
MS (Box 1), we address both aspects of inflammation
and degeneration in mediating progression. In addi­
tion to medications that target the inflammatory and
degenerative aspects, we also discuss medications that
promote remyelination8, given that re-formed myelin
might restore trophic support to denuded axons to slow
Neuromyelitis optica axonal degeneration. Although the focus of this Review
spectrum disorder is on progressive MS, we also refer to important relevant
Inflammatory disorder of
data from other inflammatory and neurodegenerative
the central nervous system
mediated by disease-specific conditions, such as neuromyelitis optica spectrum disorder,
antibodies against owing to similarities in their pathological mechanisms.
aquaporin-4, leading to As the study populations investigated in different trials
severe immune-mediated differed considerably regarding their inclusion criteria
demyelination and axonal
damage.
(for example, SPMS with or without relapse activity, or
PPMS) and changed over time, comparison of the results
Normal-appearing white of different studies is difficult.
matter
(NAWM). An area in the white
Targeting neuroinflammation
matter without obvious lesions
or significant abnormalities, RRMS is characterized by immune cell-driven,
such as axonal damage, plaque-like demyelination with consequent neuro­
astrogliosis and microgliosis. degeneration9, whereas the invasion of T cells into the
CNS parenchyma is markedly lower — albeit still present
Normal-appearing grey
matter
— in progressive MS10. Moreover, in progressive MS,
(NAGM). An area in the grey inflammation is deemed to be compartmentalized at
matter without obvious lesions. both the leptomeningeal and the blood vessel levels
within the CNS parenchyma, as few breaches seem to
exist in the blood–brain barrier 11,12. Infiltration of
monocytes — which differentiate into macrophages
— and local activation of microglia is seen in all types
of MS, but the macrophage/microglia representation
is more pronounced in progressive MS, and these cells
seem to drive the expansion of established lesions13.
The normal-appearing white matter (NAWM) contains
diffuse microglial inflammation with few hypercellular
lesions and inflammatory perivascular cuffs14. In addition,
oxidative injury (including to mitochondria), which is
prominently contributed to by macrophages/microglia,
is prevalent in progressive MS lesions12.
Given that progressive MS is characterized by a
mostly intact blood–brain barrier, medications for pro­
gressive MS that target pathophysiological features of
progressive MS should cross the blood–brain barrier,
have the capacity to inhibit the activity of microglia,
reduce oxidative stress and retain the capacity to alter
the activity of T lymphocytes and B lymphocytes (Fig. 1).
Targeting T lymphocytes
The goal of therapeutic modulation of T cell composi­
tion and differentiation in progressive MS is generally to
normalize inflammation and minimize any involvement
of T cell infiltrates. T cells can be found in the spinal
cord parenchyma of patients with PPMS, but, unlike
those of patients with RRMS, these T cells are found
at lower levels and are more diffuse in the NAWM and
normal-appearing grey matter (NAGM)15. Surprisingly,
despite the low level of T cell-mediated inflammation
in progressive MS lesions, levels of inflammatory mark­
ers of T cell activation in cerebrospinal fluid (CSF) are
comparable between patients with progressive MS and
those with RRMS16. In contrast to these low levels of
T cells in the parenchyma of patients with progressive
MS, increased numbers of T cells are located within the
meninges in patients with progressive MS. The extent
of meningeal T cell inflammation is correlated with
axonal loss in the NAWM15, suggesting that the detri­
mental role of T cells in progressive MS is potentially
mediated by long-range soluble factors. In progressive
MS forms, T cells slowly accumulate in spaces con­
necting the lepto­meninges to the parenchyma, such as
Virchow–Robin spaces and meninges17. This finding
might indicate that progressive MS is not characterized
by a lack of T cell activation, but rather by exclusion of
T cells from the brain and spinal cord parenchyma. In
addition, tissue-resident memory T cells, such as the few
that are found in the CNS parenchyma of patients with
progressive MS, tend to have downregulated expression
of S1PRs compared with central memory or effector
memory T cells18, which is prob­ably why these cells are
retained in tissues and not targeted by S1PR modulators
such as fingolimod or siponimod12.
Targeting T cells to slow disease progression remains
difficult, as demonstrated by the negative findings of
the phase III ASCEND trial, in which natalizumab, an
antibody directed against the α4 integrin subunit, failed
to reduce confirmed disability progression compared
with placebo in patients with SPMS19. However, several
interesting approaches could effectively target T cells,
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 Reviews

Mitochondrion-protective strategies

• Minocycline
Fe2+ • Chelating drugs
• Antioxidants

Brain

Anti-inflammatory strategies

• Riluzole
• Memantine
• Amantadine Siponimod
Astrocyte
Strategies targeting B and T lymphocytes
Glutamate
S1PR

Lactosylceramide

Inhibitor
ROS/
RNS Microglia

CD20 • Dimethyl fumarate

• Ocrelizumab • Minocycline
• Rituximab • Dextromethorphan
• Hydroxychloroquine
Meningeal
B cells

CD52
Remyelination strategies
GZ402668
Denuded axon

Lymphocyte
Amiloride Opicinumab LINGO1

Statins
ASIC1

MIF
Ibudilast

Macrophage Na+ channels

Lamotrigine • MD1003
HSC or MSC transplantation • Domperidone
• Clemastine

HSC MSC
Fig. 1 | Treatment approaches for progressive Ms. Mitochondrion-
protective strategies include the use of minocycline, iron (Fe2+)-chelating
compounds and antioxidants that reduce oxidative stress. Anti-
inflammatory strategies targeting microglia and astrocytes include
the S1PR modulator siponimod, which is licensed by the US Food and
Drug Administration as therapy for secondary progressive multiple
sclerosis (SPMS), and inhibitors of microglial activity, including dimethyl
fumarate, minocycline, dextromethorphan and hydroxychloroquine.
Axonoprotective approaches targeting ion channels include amiloride and
lamotrigine. Remyelination therapies are being tested with the leucine-rich
repeat neuronal protein 1 (LINGO1)-targeted antibody opicinumab,
domperidone (which elevates prolactin levels) and the first-generation
antihistamine clemastine (which targets muscarinic receptors). MD1003
(biotin) is postulated to promote remyelination through its function as a
co-enzyme for carboxylases that might promote the synthesis of myelin
lipids. Strategies targeting lymphocytes include the CD20-targeting
antibodies ocrelizumab (which is approved for primary progressive
multiple sclerosis (PPMS)) and rituximab. Other lymphocyte-targeting
approaches include the use of the anti-CD52 antibody GZ402668 and the
phospho­diesterase inhibitor ibudilast, which targets migration inhibitory
factor (MIF). Stem cell transplantation, including haematopoietic stem cell
(HSC) or mesenchymal stem cell (MSC) transplantation, is another method
of normalizing T cell populations. RNS, reactive nitrogen species; ROS,
reactive oxygen species.

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Table 1 | ongoing and completed clinical trials in progressive Ms

Treatment Trial details and status Patients Primary end points secondary end points
Neuroprotection and remyelination
Laquinimod Phase II (NCT02284568); completed PPMS PBVC • Time to CDP
October 2017 • Change from baseline in T25FW
• Number of new T2 brain lesions
Amiloride, fluoxetine, Phase IIb (MS-SMART; NCT01910259); SPMS MRI-derived PBVC • T2 lesions
riluzole active, not recruiting; final results • Pseudoatrophy
pending • Clinical measures of
neuroprotection
Oxcarbazepine Phase II (PROXIMUS; NCT02104661); Definite MS NFL levels in CSF • Safety
completed January 2018 • Clinical outcome (neurological
examination)
• Cognition
Domperidone Phase II (NCT02308137); recruiting; SPMS T25FW • 9HPT
planned study end date January 2020 • EDSS
• MFIS
• MS quality of life
Biotin (MD1003) Phase III (NCT02936037); active, not PPMS and • EDSS • 12-weeks confirmed EDSS
recruiting; planned study end date SPMS • T25FW progression
June 2023 • CGI-I score
Caprylic triglyceride Phase II (NCT01848327); completed RRMS, SPMS • Changes in learning • EDSS
December 2017 and PPMS • SDMT • BDI-II
• MSQOL-54
• MFIS
Liothyronine Phase Ib (NCT02506751); completed MS Adverse events –
September 2017
Idebenone Phase I/II (IPPoMS; NCT00950248); PPMS Inhibition of brain atrophy Inhibition of individualized rates
completed August 2018 (SIENA) of development of brain atrophy
Phase I/II (NCT01854359); active, not PPMS Inhibition of brain atrophy Inhibition of individualized rates
recruiting; planned study end date (SIENA) of development of brain atrophy
August 2019
Lipoic acid Phase II (NCT03161028); recruiting; Progressive T25FW • 2-minute timed walk
planned study end date April 2021 MS • Fall count
• Brain atrophy
B cell-targeted or T cell-targeted agents
Rituximab (intravenous Phase II (EFFRITE; NCT02545959); PPMS and Change in osteopontin level • TNF, neurofilament and IgG levels
and intrathecal), status unknown; planned study end SPMS in CSF in CSF
methylprednisolone date September 2019 • Brain volume atrophy (SIENA)
(intravenous)
GZ402668 Phase I (NCT02977533, Progressive Adverse events • Cmax
NCT02313285); completed, MS • AUC
open-label follow-up; planned study • Lymphocyte depletion
end date April 2022 • Anti-drug antibodies
• Injection site reactions
Simvastatin Phase II (MS-OPT; NCT03896217); not SPMS Effect on cerebral • MRI: glutamate levels and brain
yet recruiting; planned study end date blood flow atrophy
January 2021 • EDSS and functional scores
Stem cell therapy
Biological: human Phase I/II (NCT01364246); status PPMS and EDSS • VEP
umbilical cord unknown; planned study end date SPMS • SEP
mesenchymal stem cells December 2014 • BAEP
• Changes in MRI
HSC therapy Phase III (NCT00273364); active, not MS (not EDSS progression • Number of relapses
recruiting; planned study end date further • MSFC, PASAT and others
September 2024 specified)
Autologous Phase I/II (EMMES; NCT02495766); RRMS or Adverse events and safety • Cumulative number of
mesenchymal active, not recruiting; planned study SPMS profiles gadolinium-enhancing lesions
stromal cells end date June 2020 • MS outbreaks
(XCEL-MC-ALPHA) • EDSS
• Cumulative T2 lesions
Bone marrow Phase II (ACTiMuS; NCT01815632); PPMS and GEP • Safety
transplantation recruiting; planned study end date SPMS • EDSS
October 2019 • MSFC
• MRI brain and spinal cord
(lesion load and atrophy)
• OCT

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Table 1 (cont.) | ongoing and completed clinical trials in progressive Ms

Treatment Trial details and status Patients Primary end points secondary end points
Stem cell therapy (cont.)
Autologous Phase II (NCT02166021); status RPMS and • Brain MRI • EDSS
mesenchymal bone unknown; planned study end date SPMS • Immunological response • Neurological function
marrow stem cells March 2018 • Electrophysiology
Tolerogenic dendritic Phase I (TOLERVIT-MS; RRMS and • Safety • ARR
cells NCT02903537); recruiting; planned SPMS with • EDSS score changes • EDSS
study end date September 2019 relapse • Number of new T2 lesions • 9HPT
activity and gadolinium-enhancing • T25FW
lesions
Interventions targeting inflammation
Masitinib Phase IIb/III (NCT01433497); active, PPMS and MSFC • EDSS
not recruiting; planned study end SPMS • MSQOL-54
date September 2020 • T25FW
• 9HPT
Methotrexate Early phase I (ITMTXPMS; – • Change in disability • Changes in brain MRI
(intrathecal) NCT02644044); status unknown; • Safety and tolerability measurements
planned study end date January 2018 • Laboratory measurements
Dimethyl fumarate Phase IV (SURV-SEP; NCT02901106); RRMS, SPMS • Relapse –
terminated October 2017 and PPMS • EDSS
Phase II (FUMAPMS; NCT02959658); PPMS NFL • EDSS
active, not recruiting; planned study • T25FW
end date December 2019 • 9HPT
• SDMT
Hydroxychloroquine Phase II (NCT02913157); PPMS T25FW • 9HPT
recruiting; planned study end date • EDSS
December 2020 • SDMT
• MFIS
Andrographolide Phase I/II (NCT02273635); status SPMS and Brain atrophy • EDSS
unknown; planned study end date PPMS • PASAT
April 2017 • MSIS29
• New T2 lesions
Ibudilast Phase II (NCT01982942); completed PPMS and • Mean rate of change in brain Diffusion tensor imaging,
December 2017 SPMS atrophy over 96 weeks magnetization transfer ratio,
• Safety measures retinal nerve fibre layer (OCT),
cortical atrophy
MIS416 Phase IIb (NCT02228213); completed SPMS Change from baseline of SAEs
June 2017 neuromuscular function at 12
months (MSFC and other tests)
Miscellaneous interventions
Oestrogen Phase II (NCT01466114); unknown RRMS, SPMS Changes in cognition (PASAT) • EDSS
status; planned study end date and PPMS • T25FW
December 2018
ACTH Phase II (NCT01950234); recruiting; SPMS, PPMS Proportion of patients • Safety and tolerability
planned study end date March 2020 and RPMS exhibiting a 20% worsening in • Slowed progression of cognitive
T25FW at 36 months disability
• Retinal nerve fibre layer thickness
NeuroVax (TCR Phase II/III (NCT02057159); unknown SPMS Cumulative number of new • Relapses
peptide vaccine) status; planned study end date gadolinium-enhancing lesions • EDSS
February 2019 on brain MRI • Immunological evaluation
• Safety
ABT-555 (antibody Phase I (NCT02601885); completed RRMS and • Adverse events • T25FW
against RGMa) April 2018 SPMS • Pharmacokinetics and • 9HPT
pharmacodynamics • Quality of life
• T1 gadolinium-enhancing lesions
Methylprednisolone Phase I (MSECP; NCT02296346); SPMS Accumulation of disability Changes in immunological
via extracorporeal recruitment suspended; planned (composite of components of parameters
photopheresis study end date October 2017 MSFC score)
Insulin (intranasal) Phase I/II (NCT02988401); recruiting; RRMS, SPMS Change in SDMT • Safety
planned study end date June 2020 and PPMS • Cognition
9HPT, 9-Hole Peg Test; ACTH, adrenocorticotropic hormone; ARR, annualized relapse rate; AUC, area under the curve; BAEP, brainstem auditory evoked potential; BDI-II,
Beck depression inventory 2nd edition; CDP, confirmed disability progression; CGI, Clinical Global Impression rating scales; CSF, cerebrospinal fluid; EDSS, Expanded
Disability Status Scale; GEP, global evoked potential; HSC, haematopoietic stem cell; MFIS, Modified Fatigue Impact Scale; MSFC, Multiple Sclerosis Functional
Composite; MSIS29, Multiple Sclerosis Impact Scale; MSQOL-54, Multiple Sclerosis Quality Of Life-54; NFL, neurofilament light chain; OCT, optical coherence tomography ;
PASAT, Paced Auditory Serial Addition Test; PBVC, percentage brain volume change; PPMS, primary progressive multiple sclerosis; RGMa, repulsive guidance molecule a;
RRMS, relapsing–remitting multiple sclerosis; SAE, serious adverse event; SDMT, Symbol Digit Modalities Test; SEP, somatosensory evoked potential; SIENA, structural
image evaluation using normalization, of atrophy ; SPMS, secondary progressive multiple sclerosis; T25FW, Timed 25-Foot Walk; VEP, visual evoked potential.

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Experimental autoimmune
encephalitis
(EAE). An inflammatory animal
model of multiple sclerosis,
mediated by inoculation of
myelin components with
adjuvants.
Gadolinium-enhancing
lesions
T1 lesions showing
contrast agent (gadolinium)
enhancement on magnetic
resonance imaging.
T2 lesions
Hyperintense magnetic
resonance imaging sequences,
indicating multiple sclerosis
lesion load.
a number of which are under investigation in ongoing or
completed trials (Fig. 1; Table 1).
Statins. One therapeutic option to modulate T cell activ­
ity in progressive MS is the use of statins. Simvastatin has
anti-inflammatory effects and can induce a shift from
a pro-inflammatory T helper type 1 (TH1) phenotype
to a less-damaging, anti-inflammatory TH2 phenotype20.
Simvastatin reduces the number of T H1 cells and
TH17 cells (the latter of which are particularly pro-
inflammatory), improves clinical scores in the inflam­
matory experimental autoimmune encephalitis (EAE)
model of MS21, and inhibits the in vitro TH17 differen­
tiation of CD4+ T cells isolated from patients with MS22.
In addition, statins induce remyelination in the spinal
cord of EAE animals23.
In one Cochrane review that included four trials
including 458 patients, the combination of simvastatin
or atorvastatin with interferon-β (IFNβ) did not reduce
relapses, disease progression or the development of
gadolinium-enhancing lesions 24. In the randomized,
double-blind, placebo-controlled phase II MS-STAT
trial, simvastatin (80 mg daily) reduced the number of
new and enlarging T2 lesions (2.19 versus 1.50 events
per person-year; P = 0.176) and the rate of brain atrophy
(0.288% versus 0.584% per year; P = 0.003) compared
with placebo in patients with SPMS25. In a sub-analysis
of MS-STAT trial data, patients on treatment experi­
enced improvements in frontal lobe function, as meas­
ured using the Frontal Assessment Battery score and
the mean physical component score, a subscale of the
self-reported 36-item Short Form Survey (SF-36)26.
The contradictory results of the MS-STAT trial (positive)
and the Cochrane meta-analysis (negative) could be
because of the use of different outcome parameters:
the MS-STAT study used brain atrophy, which is pre­
sumably more valid in patients with progressive MS.
Thus, statin therapy might both induce neuroprotection
and target T cell-mediated inflammation.
To further address potential effects on progression, a
group at University College London announced the phase
II MS-OPT trial in patients with SPMS (NCT03896217),
which started recruitment in March 2019 (Table  1).
This double-blind, randomized, placebo-controlled
single-site study will evaluate the effects of simvasta­
tin (80 mg daily) on cerebral blood flow (the primary
end point), but also on brain atrophy and Expanded
Disability Status Scale (EDSS) and functional scores
(secondary end points). However, given that the utility
of cerebral blood flow as a good marker of neuroprotec­
tion is highly speculative, the results of the MS-OPT trial
could be challenging to interpret.
Stem cell transplantation. Another means to normalize
the T cell populations in patients with progressive MS is
via stem cell transplantation (SCT). A number of studies
evaluating stem cell therapy for progressive MS are ongo­
ing or have been completed (Table 1). Of note, the stud­
ies discussed herein were performed using different SCT
protocols, which vary in their mechanisms of action,
efficacy and adverse effect profiles. Preclinical studies
support this approach; for instance, transplantation
of mesenchymal stem cells (MSCs) in EAE models
improved clinical scores, and the improvement was cor­
related with the generation of classical regulatory T (Treg)
cells in an IL-17A-dependent manner27.
Regarding autologous bone marrow transplanta­
tion, one study in patients with PPMS showed that this
treatment is relatively safe and a small phase I trial in six
patients with progressive–relapsing MS (an old classifica­
tion to describe patients who are relapsing but also pro­
gressing) found that treatment normalized or improved
EDSS scores over 1 year28. In a phase IIa proof-of-
concept study, autologous bone marrow transplantation
improved visual acuity and visual evoked potentials
and increased optic nerve area in patients with SPMS
who had visual impairment29. A phase III randomized
controlled trial evaluating bone marrow-derived cellular
therapy in patients with progressive MS (ACTiMuS) has
been underway since March 2014 (ref.30) (Table 1).
In addition, delivery of autologous haematopoietic
stem cells (HSCs) reduced T2 lesions in patients with
SPMS and RRMS, but did not slow progression of disa­
bility31. This approach is currently being investigated in a
phase III clinical trial (NCT00273364; Table 1). In 2019,
Burt and colleagues32 reported the efficacy of nonmyelo­
ablative HSC transplantation (HSCT) compared with
continued disease-modifying therapy (DMT) in patients
with RRMS. While patients who received nonmyelo­
ablative HSCT had a decrease in mean EDSS score after
1 year (from 3.38 to 2.36) and only three patients had
progressed after 1 year, DMT-treated patients had a
higher mean EDSS score after 1 year (from 3.31 to 3.98)
and 34 patients had disability progression (median time
to progression 24 months). Muraro et al.33 retrospec­
tively evaluated long-term outcomes in 281 patients from
25 centres after autologous HSCT following treatment
with a low-intensity regimen (cyclophosphamide alone or
in combination with anti-thymocyte globulin or fludara­
bine) or a high-intensity regimen (busulfan or total-body
irradiation). Of the 281 patients, 78% had progressive
forms of MS, and, interestingly, older patients and patients
with progressive disease were more likely to progress rel­
ative to those with RRMS (HR 1.03, 95% CI 1.00–1.05,
and HR 2.33, 95% CI 1.27–4.28, respectively)33, rais­
ing the concern that this therapeutic approach is only
applicable to younger patients with early stage disease
and presumably has limited efficacy in patients with
progression. Another approach under investigation in
ongoing trials is the use of MSCs derived either from the
umbilical cord (phase I and II; NCT01364246) or from
adipose tissue (phase I; NCT02326935; Table 1).
Thus, increasing evidence suggests that SCT may be
able to reduce MS progression, but long-term data are
needed to better evaluate whether such reprogramming
of the immune system is a good therapeutic approach
for progressive MS. Moreover, differing protocols and
methods exist (for example, nonmyeloablative versus
myeloablative SCT, and transplantation of different
cell types), the relative efficacy of which remains to be
established. Future investigations of the effects of SCT on
compartmentalized meningeal inflammation associated
with neurodegeneration, which has not been done to the
best of our knowledge, might also be interesting.
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Targeting B lymphocytes
B cells have multiple roles and contribute to progres­
sion in MS34 via antibody production, antigen presenta­
tion to T cells35 and the secretion of pro-inflammatory
cytokines36. Studies of brains from individuals who died
with progressive MS have demonstrated increased cellu­
lar inflammatory aggregates, particularly in the menin­
ges, some of which are enriched with B cells and have
been referred to as ectopic follicles37. The importance of
this meningeal B cell accumulation is demonstrated by
reports of subpial grey matter demyelination and micro­
glial activity in cortical structures38–40. Meningeal B cell
accumulation seems to be clinically relevant as patients
with B cell follicular structures have a faster progression
of disability, an earlier disease onset and a younger age at
death than those without such structures38. In progres­
sive MS, the presence of a subset of B cells (DC-SIGN+
B cells) and T helper cells (ICOS+ TFH– cells) correlates
with disease progression, suggesting the presence of
ongoing peripheral inflammation41. Furthermore, clo­
nally expanded plasma cells from patients with MS pro­
duce antibodies directed against neurons and astrocytes,
but rarely against myelin; however, these antibodies lead
to demyelination in murine spinal cord slice cultures,
stressing the pathological role of clonally expanding
B cells in progressive MS42.
On the contrary, new evidence shows that the num­
ber of IgA+ plasma cells is reduced in the gut during EAE,
and that over-abundance of IgA+ plasmablasts or plasma
cells leads to resistance against EAE development43.
These observations are in line with the findings of a
clinical study in patients with RRMS, in which weekly
treatment with atacicept — a soluble fusion protein
containing a fragment of transmembrane activator and
CAML interactor (TACI; a TNF receptor superfamily
member) that binds to B lymphocyte stimulator (BLYS;
also known as BAFF) and a proliferation-inducing
ligand (APRIL) — led to deterioration with a higher
annualized relapse rate in the atacicept groups (25 mg,
0.86, 95% CI 0.43–1.74; 75 mg, 0.79, 95% CI 0.40–1.58;
and 150 mg, 0.98, 95% CI 0.52–1.81) than in the placebo
group (0.38, 95% CI 0.17–0.87)44. These data show that
the role and type of plasma cells or different lineage pre­
cursor stages of B cells in different organs can be either
beneficial or deleterious, speaking to the complexities
of potential therapeutic approaches. Thus, B cell deple­
tion has been considered a promising approach to the
treatment of progressive MS and is under current clinical
investigation (Fig. 1; Table 1).
Anti-CD20 antibodies. Although in the OLYMPUS
study intravenous infusion of the CD20-specific anti­
body rituximab failed to improve the primary end point
of confirmed disability progression compared with pla­
cebo in patients with progressive MS, subgroup analyses
showed partial efficacy in patients who were younger
than 51 years and/or had gadolinium-enhancing
lesions45. However, B cell depletion with rituximab does
not change oligoclonal bands46, implying that meningeal
B cell clones, for example, are not completely depleted, or
that the disappearance of oligoclonal bands has limited
diagnostic value in predicting progression. Moreover,
Nature Reviews | Drug Discovery
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long-lived plasma cells are not targeted by rituximab
because these cells downregulate CD20. Whether the
beneficial depletion of peripheral B cells or B cell clones
with rituximab in the stated OLYMPUS subgroups
occurred in the meninges or the brain is unclear, because
only a low amount of rituximab (0.1%) passes the
blood–brain barrier after intravenous administration47.
Intrathecal administration of rituximab might
improve the targeting of B cells in the brain and menin­
ges. Indeed, after intrathecal injection of even very low
doses of rituximab (two injections of 3.5 mg), exten­
sive peripheral B cell depletion occurred in patients
with progressive MS48. Of note, combined peripheral
and intrathecal administration of rituximab is cur­
rently under investigation (NCT02545959; Table 1).
In the RIVITaLISe study, combined intravenous and
intrathecal administration of rituximab in patients with
SPMS, led to a robust depletion of B cells in the CSF49.
However, levels of neurofilament light chain and other
biomarkers were unchanged, and therefore the study was
stopped. The authors hypothesized that the study might
have been underpowered to detect treatment effects,
especially regarding the biomarkers investigated.
In a retrospective propensity-matched cohort
study in 44 matched pairs of patients with SPMS,
rituximab-treated patients had a significantly lower
mean EDSS score (mean difference –0.52, 95% CI –0.79
to –0.26; P < 0.001) and a delay in time to confirmed
disability progression (HR 0.49, 95% CI 0.26–0.93;
P = 0.03) than patients never treated with rituximab50.
Positive findings of the placebo-controlled ORATORIO
trial provide evidence that B cell depletion using the
CD20-targeting antibody ocrelizumab might indeed be
efficacious in patients with PPMS6. The study included
732 patients with PPMS and showed a 24% reduced
risk of disability progression 12 weeks after treatment
with 600 mg ocrelizumab and a 17.5% reduced rate of
brain atrophy. These findings were accompanied by less
worsening of the Timed 25-Foot Walk (T25FW) after
120 weeks in the ocrelizumab group than in the placebo
group (38.9% versus 55.1%; P = 0.04). In March 2017,
ocrelizumab received market authorization from the
FDA and European Medicines Agency (EMA) and is,
therefore, the first medication approved for PPMS — a
milestone in MS therapy.
Anti-CD52 antibodies. Another approach is to simultane­
ously target T and B lymphocytes using next-generation
antibodies directed against CD52 (which is expressed on
both T and B cells), with the goal of reducing immuno­
genicity and infusion-related events compared with
the currently used CD52-targeting antibody alemtu­
zumab (which is approved for the treatment of highly
active RRMS). The next-generation anti-CD52 anti­
body GZ402668 binds to different CD52 epitopes than
those targeted by alemtuzumab, and it reduces the
levels of tumour necrosis factor (TNF) and IFNγ, and
dose-dependently decreases lymphocyte numbers in vivo
in CD52-humanized mice51. Currently, the antibody is
under investigation in a phase I trial in patients with pro­
gressive MS and in an open-label, long-term follow-up
study (NCT02977533 and NCT02313285; Table 1).
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Targeting myeloid cells
Microglia have a crucial role in the homeostasis of the
brain but also have an important role in the progression
of MS52. Activated microglia and monocyte-derived
macrophages are often indistinguishable from one
another in pathology studies, and are often collec­
tively termed ‘macrophages/microglia’. Microglia and
macrophages are generally assumed to differ in their
phenotype and function, but, because of the histori­
cal challenges in differentiating these cells, their rela­
tive contribution to MS is unclear. Nonetheless, these
cells are prominent producers of ROS and RNS and
pro-inflammatory cytokines and chemokines.
In patients with MS, activation of macrophages/
microglia occurs in the NAWM and NAGM, corre­
lating with axonal injury14. In mouse models, release
of ROS or RNS from macrophages can initiate focal
axonal degeneration, even if myelin sheaths are intact53.
In EAE, NADPH oxidase activity in microglia and
astrocytes has been shown to remain high after peak
disease into the chronic setting, suggesting the ongo­
ing production of ROS54; elevated NADPH oxidase
activity is associated with increased neuronal calcium
(Ca2+) levels, which might indicate impaired neuronal
function, and is also associated with ROS production
by macrophages/microglia. Moreover, ageing-related
phenotypic changes have been reported in macrophages/
microglia. Indeed, microglia from aged mice are
more prone to generation of neurotoxins than those
from neonatal mice55 and, in post mortem analyses of
patients with MS, microglia displayed ageing-related
morphological changes with less ramified morpho­
logy56. This finding links the observations that most
patients with RRMS develop a progressive phenotype
only 15–20 years after disease onset and that progres­
sion of disability occurs at a similar age in both SPMS
and PPMS.
In addition to ROS, macrophages/microglia are major
sources of pro-inflammatory cytokines and chemokines.
These cells can adopt many polarized states, including
pro-inflammatory or regulatory, anti-inflammatory
phenotypes; however, the categorization into M1 and
M2 phenotypes is oversimplified57. In the Theiler’s murine
encephalomyelitis virus infection model of MS, the early
phase is dominated by pro-inflammatory macrophages/
microglia, whereas the chronic–progressive phase is
characterized by regulatory and/or anti-inflammatory
polarization with sustained pro-inflammatory forms58.
Thus, normalization of macrophage/microglia func­
tion is a promising therapeutic approach, given that a
switch towards a regulatory, anti-inflammatory pheno­
type promoted oligodendrocyte differentiation and led
to enhanced remyelination in the lysolecithin mouse
model59. Indeed, a number of therapeutic approaches
have been investigated (Fig. 1; Table 1).
Inhibitors of macrophage/microglia activity. Hydroxy­
chloroquine, an antimalarial medication that is also
used in rheumatoid arthritis, has been shown to
inhibit the lipopolysaccharide-induced production of
pro-inflammatory cytokines by microglia concomitant
with attenuation of EAE in mice60. This agent is currently
under investigation in a phase II trial in patients with
PPMS (NCT02913157; Table 1).
The compound MIS416, which targets myeloid cells
via activation of the cytosolic receptors nucleotide-
binding oligomerization domain-containing protein 2
(NOD2) and Toll-like receptor 9 (TLR9), reduced dis­
ease severity in a mouse EAE model of MS61 and is
currently being evaluated in a phase IIb trial in SPMS
(NCT02228213).
Another approach uses the phosphodiesterase inhibi­
tor ibudilast, which targets macrophage migration
inhibitory factor (MIF)62 and might, therefore, affect
trafficking of macrophages into the CNS. Ibudilast has
been investigated in a phase II trial, which included a
total of 255 patients with PPMS or SPMS63,64; the primary
end point was the rate of change in the brain parenchy­
mal fraction. Over 96 weeks, patients in the ibudilast arm
(n = 129) experienced ~2.5 ml less brain tissue loss than
those in the placebo arm (n = 126)64. However, whether
this effect is clinically relevant for disability or cognitive
function remains to be investigated in future trials.
Antioxidants. Another therapeutic approach for pro­
gressive MS is to target the release of ROS and RNS from
myeloid cells. Inhibiting the ROS-generating enzyme
NADPH oxidase 2 (NOX2) with low-dose dextromethor­
phan treatment led to an improved disease course in the
EAE mouse model65. Importantly, NOX2 is expressed
at high concentrations in microglia and macrophages,
and its inhibition with dextromethorphan can increase
the proliferation of oligodendroglial precursor cells
fourfold66 and attenuate microglial activity, leading to
decreased production of nitric oxide (NO), superoxide
free radicals and TNF67.
An agent with auspicious preclinical and clinical
data is lipoic acid, an endogenously produced antioxi­
dant with numerous physiological roles. Lipoic acid was
investigated in a small study in patients with SPMS68.
After 2 years, the annualized percentage change in brain
volume was significantly lower in the lipoic acid arm
(n = 27; 1,200 mg lipoic acid daily) than in the placebo
arm (n = 24; –0.21 versus –0.65; P = 0.002). Currently, this
approach is being investigated in a phase II multi-centre
clinical trial (NCT03161028; Table 1).
A medication with pleiotropic mechanisms of action,
including antioxidant activity, is dimethyl fumarate
(DMF). Indeed, DMF has cytoprotective effects in
immune cells, glia and neurons (for reviews see refs69,70).
DMF modifies the Kelch-like ECH-associated protein 1
(KEAP1)–nuclear factor erythroid 2-related factor 2
(NFE2L2) complex, thereby reducing oxidative stress
and promoting cytoprotection71. Owing to these effects,
the use of DMF for the treatment of PPMS has been
investigated. A small observational study in 26 patients
treated with either fumaderm (a mixture of fumaric acid
esters; n = 18) or DMF (n = 8) showed that 75% of the
patients either remained stable or had a slightly reduced
EDSS score (that is, improvement in disability), whereas
no differences were found between the two pharma­
ceutical forms72. Since 2016, the phase II FUMAPMS
study has investigated use of DMF in the treatment of
PPMS (Table 1).
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Clinically isolated syndrome
(CIS). The first clinical episode
of neurological symptoms
lasting at least 24 h, with
features that are indicative
of multiple sclerosis.
Astrogliosis
An increase in the number of
astrocytes due to damage.
Nature Reviews | Drug Discovery
Targeting cytokines. In addition to the production of
ROS, pro-inflammatory cytokine secretion remains
prevalent during progressive MS. Infiltrating macro­
phages contribute to progressive MS through sustained
production of TNF, as shown in a mouse model of pro­
gressive EAE, in which treatment with an anti-TNF
agent reduced myelin loss and leukocyte infiltration73.
However, demyelinating neurological disease was
reported after treatment with an anti-TNF agent in
patients with rheumatological disease74, and a study
in 168 patients, most with RRMS, showed increased
and earlier exacerbations of MS in patients receiving
the TNF-blocking agent lenercept compared with those
receiving placebo75. However, the pathology underlying
these observations remains elusive. TNF production
by microglia is enhanced by galectin-9, which is pro­
duced by astrocytes76. Galectin-9 is elevated in the CSF
of patients with SPMS and correlates with T1 lesion load,
but not with gadolinium-enhancing lesions, IgG index
or CSF cell count, supporting the concept of sustained
compartmentalized inflammation by resident innate
immune cells in progressive MS77.
Another pro-inflammatory cytokine involved in pro­
gressive MS is IL-6, the production of which is sustained
during the chronic phase of EAE in astrocytes and the
blockade of which results in decreased disability, myelin
loss and axonal damage, as well as reduced activation
of microglia in a progressive EAE model78. Despite the
evidence of successful therapy using the IL-6-blocking
antibody tocilizumab in neuromyelitis optica79,80, there is
only limited experience in MS81. Alarmingly, one report
described the development of MS in a patient with rheu­
matoid arthritis receiving tocilizumab therapy, although
this patient had prior treatment with TNF-blocking
therapy, which is known to induce demyelination82.
Thus, further studies are warranted to investigate
whether IL-6-targeted therapy is effective in reducing
progression in MS.
Another medication that has potential for use in the
treatment of progressive MS is minocycline, a widely
used tetracycline with a good safety profile. This agent
inhibited the activity of matrix metalloproteinases
(MMPs), decreased MMP-9 production and led to an
improved disease course in a mouse model of EAE83. In
addition, minocycline has been shown to reduce micro­
glial TNF production during T cell–microglia interaction
by downregulation of CD40 ligand (CD40L) expression
on T cells84. Minocycline treatment exerted positive
effects in both acute and chronic EAE animal models85,86.
However, the findings of studies in humans have partially
contradicted the preclinical findings. While minocycline
has been reported to have positive effects in RRMS87 and
to reduce the risk of developing definite MS in patients
with clinically isolated syndrome (CIS)88, this decreased
risk of conversion to MS in CIS is lost after 24 months88.
Furthermore, in the RECYCLINE study, the addition of
minocycline to IFNβ1a in patients with RRMS did not
show any additional effect regarding time to first qual­
ifying relapse beyond that of IFNβ1a plus placebo89.
Although the minocycline CIS trial (at 24 months) and
the RECYCLINE trial were underpowered, the proposed
mechanisms of action — which include the inhibition of
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microglial cytokine production84 — support the rationale
for further evaluation of minocycline in progressive MS.
Targeting astrocytes
Evidence from chronic EAE studies supports the role
of astrocytes in promoting chronic inflammation.
Astrocytes are the most abundant cell type in the CNS.
They have a crucial role in neural development and
function, and contribute to MS pathophysiology due to
scar formation and release of inflammatory mediators90.
Activated ‘A1’ astrocytes can be induced by microglial
secretion of IL-1α, TNF and complement C1q. These A1
astrocytes lose the ability to promote neuronal survival,
outgrowth and synaptogenesis, and, instead, induce
the death of neurons and oligodendrocytes91. Another
study found that microglia-derived vascular endothe­
lial growth factor (VEGF) triggers pro-inflammatory
signalling in astrocytes and worsens EAE, whereas
microglia-derived transforming growth factor-α
(TGF-α) suppresses the pathophysiological activity of
astrocytes92. In an EAE model of MS, the genetic dele­
tion of astrocytes in the acute phase of disease worsened
disease severity, but their depletion during the chronic
progressive phase ameliorated disease activity93. Thus,
astrocytes with pro-inflammatory and neurotoxic
activities are thought to contribute to pathology in the
progressive phase of MS.
In astrocytes, the glycosphingolipid lactosylceramide
— which is synthesized by the enzyme β-1,4-galacto­
syltransferase 6 (B4GALT6) — functions in an auto­
crine manner to activate the nuclear factor-κB (NF-κB)
and interferon regulatory factor 1 (IRF1) pathways,
leading to the production and release of C-C motif
chemokine 2 (CCL2) and granulocyte–macrophage
colony-stimulating factor (GMCSF), which subsequently
activate microglia and monocytes93. Inhibition of lacto­
sylceramide synthesis markedly improved behavioural
outcomes in a chronic progressive EAE mouse model,
and was associated with reduced neurodegeneration93.
Another way to block astrocyte activity is through
therapeutic modulation of the S1PRs, which induce
astrocyte proliferation upon activation by sphingosine-1-
phosphate (S1P)94. Indeed, down-modulation of S1PR1
(also known as S1P1) leads to reduced astrogliosis95, and
treatment of astrocytes with S1P inhibits gap junctions
between astrocytes via activation of both Gi and Rho
GTPases96. Treatment of EAE mice with fingolimod, a
modulator of S1PR1–5 (also known as S1P1–5), during
the chronic phase reduced astrogliosis, demyelination
and axonal loss, and improved EAE97. The first phase III
trial evaluating fingolimod in patients with progressive
MS failed to meet its primary end point5. However, the
follow-up substance siponimod, another S1PR modu­
lator that has greater specificity for S1PR1 and S1PR5,
showed efficacy in the phase III EXPAND study. In
patients with SPMS, siponimod reduced 3-month con­
firmed disability progression by 21% relative to pla­
cebo7. Moreover, siponimod reduced brain atrophy by
15% (adjusted mean over months 12 and 24), suggest­
ing its neuroprotective effects7. In October 2018, both
the FDA and EMA accepted the New Drug Application
and Marketing Authorization Application for the use
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Periplaque white matter
of siponimod in the treatment of SPMS. In addition, in
The area around lesions in the March 2019, the FDA approved the use of siponimod
white matter. in the treatment of SPMS in patients with active disease
on the basis of these findings.
Iron chelation
Binding of iron by a chelating
agent. Promoting neuroprotection
Conferring neuroprotection is a key goal in reducing
axonal degeneration and neuronal loss in MS. This
approach involves interfering with mediators of injury
in the progressive phase of MS, which includes the accu­
mulation of iron, the altered expression of ion channels
and mitochondrial damage (Fig. 1).
Targeting iron
Iron accumulates in an age-dependent manner in the
CNS and has been proposed as an important contrib­
utor to the pathogenesis of progressive MS98. Indeed,
iron deposition in the deep NAGM correlates with
MS progression 99. This deposition might amplify
ongoing inflammation, exacerbate mitochondrial dys­
function through oxidative stress, potentiate axonal
damage and impair CNS homeostasis via the release
of pro-inflammatory cytokines100. Under normal phys­
iological conditions within the CNS, iron is stored
mostly in oligodendrocytes. Iron accumulates in the
CNS in patients with MS for different reasons, such
as the breakdown of iron-containing oligodendrocytes,
the infiltration of immune cells and the dysregulation of
iron-transport proteins (reviewed by Stephenson et al.98).
However, the role of iron in MS progression is contro­
versial. Although iron accumulation can contribute to
neuro­toxicity and propagation of inflammation, evidence
also suggests that iron deficiency has deleterious effects.
Indeed, compared with healthy individuals, patients with
chronic MS have decreased iron levels in the NAWM,
which corresponds with an increased disease dura­
tion101. Concurrently, iron-exporting ferroxidases are
upregulated in the periplaque white matter close to active
Box 2 | competing roles of iron in progressive Ms
In progressive multiple sclerosis (MS), competing roles of iron in mediating
neurotoxicity and neuronal restoration have been reported.
Toxic effects
Iron can elicit neurotoxic effects through the generation of reactive oxygen species (ROS)
via the Fenton reaction, leading to mitochondrial damage and neurotoxicity98. although
iron is normally stored within oligodendrocytes, it is released upon demyelination.
In regions where iron accumulates, such as the MS deep grey matter, a global reduction in
neuronal density occurs with the presence of acutely injured axons and the accumulation
of oxidized phospholipids and DNa in neurons, oligodendrocytes and axons99.
restorative effects
restorative roles of iron include its role as a cofactor for enzymes involved in
remyelination and the repopulation of oligodendrocyte lineage cells98. For instance, iron
is a cofactor for enzymes involved in cholesterol and lipid production; one example is
hydroxy-3-methylglutaryl coenzyme a reductase, which is enriched in oligodendrocytes
and catalyses the major regulatory step in cholesterol synthesis181. Other iron-containing
enzymes important for myelin synthesis and turnover include squalene epoxidase and
lipid dehydrogenases, respectively182,183. In rat pups fed an iron-deficient milk diet from
birth to 3 weeks of age, the development of myelin is delayed184. Following lysolecithin-
induced demyelination in adult mice, ferroportin-induced iron efflux from astrocytes is
required for remyelination, which occurs in part by a direct effect of iron on regeneration
of oligodendrocyte lineage cells185.
lesion edges, which suggests iron export, and are down­
regulated in the NAWM. Similarly, chronic MS lesions
have reduced iron levels101. In active MS lesions, iron is
released from dying oligodendrocytes and then taken
up by macrophages and microglia101, but whether this
removal of iron by these phagocytes is responsible for the
reduction in iron content in the chronic lesions and/or
the NAWM of patients with chronic MS, or whether it
is the result of a decreased number of iron-containing
oligodendrocytes, is unclear98. The complexities of iron
in MS are discussed in Box 2.
Decreased iron content could potentially impair the
function of iron-requiring enzymes such as glucose-6-
phosphate dehydrogenase, mitochondrial respiratory
chain enzymes or enzymes involved in the production
of lipids, which might decrease mitochondrial func­
tion and reduce remyelination98. By contrast, increased
uptake of iron by macrophages/microglia is associated
with impaired function of these cells and increased toxi­
city102. One reason for the increased uptake of iron by
macrophages/microglia could be an imbalance between
the expression of iron-importing and iron-exporting
enzymes. Evidence from EAE shows that the efflux
transporter ferroportin-1 (also known as SLC40A1)
is internalized in macrophages/microglia, leading to
increased intracellular levels of iron103. In addition,
a study using 7-T MRI in patients with MS showed that
slowly expanding lesions and some inactive lesions
have iron rims and that iron is mainly found within
pro-inflammatory macrophages/microglia 13. More
importantly, these iron-containing lesions expanded
to a greater degree over 3.5 years than lesions with­
out iron rims13. Together, these data indicate that tar­
geting the maldistribution and processing of iron is a
promising approach to the treatment of progressive
MS (Fig. 1).
One such approach is the combination of mino­
cycline with hydroxychloroquine, as both reduce the
neurotoxicity of iron in vitro and both also target other
features relevant to progression, such as mitochondrial
damage and T cell and/or B cell activation. This com­
bination has been shown to improve disease pheno­
types in the chronic EAE mouse model and the Biozzi
antibody high (ABH) progressive MS mouse model104.
Importantly, other tetracyclines do not protect neurons
from iron-mediated neurotoxicity for reasons that are
currently unknown104.
Iron chelation strategies have also been proposed as
a therapeutic avenue105. However, thus far, only pilot
studies have been performed to evaluate tolerability,
and only one patient experienced an improvement
in EDSS score using the chelator deferoxamine106,107.
However, the adverse effect profile which includes local
skin irritation, anaemia, neutropenia, agranulocytosis
and thrombocytopenia, as well as the unpleasant route
of administration (subcutaneous infusion over 6–8 h for
deferoxamine), might have hampered further investiga­
tion of this treatment avenue in larger studies. Newer
agents such as deferasirox and deferiprone are available
in oral formulation, but are still at preclinical stages of
development and, therefore, the long-term tolerability
of iron chelation strategies remains unclear.
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After screening a library of 1,040 generic medica­
tions, our group found that 35 medications reduced
iron-mediated neurotoxicity in culture108. In addition, one
of these medications, the tricyclic antidepressant clomi­
pramine, also reduced T cell and B cell proliferation and
had anti-oxidative properties. Clomipramine improved
the chronic course of EAE, including in the Biozzi ABH
mouse model of progression, and might, therefore, be a
promising candidate for progressive MS treatment108.
Targeting mitochondria
Oxidative damage to cellular structures such as mito­
chondria is present in pathological specimens from
patients with progressive MS109, and several studies
have shown an increase in the number of mitochon­
dria in both active and inactive lesions110. Additionally,
demyelination leads to an increase in size of station­
ary mitochondria and to an increase in the speed of
axonal mitochondrial transport 111. These findings
collectively infer an increased energy demand during
demyelination.
However, after remyelination, the number of mito­
chondria does not necessarily return to the number seen
under normal physiological conditions, as demonstrated
both in humans and in an animal model of demyelina­
tion112. In addition to an increased density of mitochon­
dria, an accumulation of mitochondrial DNA (mtDNA)
deletions also occurs in progressive MS, which is thought
to account for some of the susceptibility to neurodegen­
eration52. Evidence from post-mortem studies in patients
with SPMS shows that respiratory chain-deficient neu­
rons are predominantly located in layer VI and the
subcortical white matter113. Irrespective of the loca­
tion of known lesions, these neurons in post-mortem
studies contained a high number of clonally expanded
mtDNA deletions, indicating that mitochondrial dam­
age can self-replicate in a feed-forward manner; this
expansion of impaired mitochondria could further
exacerbate mitochondrial dysfunction and enhance
neurodegeneration.
Impairment of mitochondrial function is also found
in other cell types in patients with MS. Compared with
patients with Alzheimer disease and Parkinson dis­
ease, patients with MS exhibit a fourfold increase in
the numbers of respiratory enzyme-deficient choroid
plexus epithelial cells with clonally expanded mtDNA
deletions114. Enhanced choroid plexus inflammation
with consecutive mtDNA deletions could, therefore,
inform about delayed energy failure in progressive
MS. Gene therapy targeting clonally expanded mtDNA
deletions might, therefore, be an interesting approach
to the treatment of progressive MS, but is far from
clinical application.
In addition to mtDNA deletions, other mitochon­
drial defects have been associated with PPMS. Tranah
and colleagues 115 found an association between a
mitochondrial genetic variant and PPMS using
a genome-wide approach. Specifically, haplotypes J and
T were associated with an increased risk of MS. When
stratified for disease course, haplotype J was associated
with an increased risk of PPMS. This finding could,
in part, explain the reportedly higher susceptibility of
Nature Reviews | Drug Discovery
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patients with PPMS to mitochondrial malfunctioning.
Therefore, identifying and targeting mitochondrial
genes associated with the risk of developing PPMS could
be a potential approach for gene therapy. However, all
gene therapy approaches are still at a preclinical stage
of development and, therefore, whether this treatment
approach could have a clinically meaningful effect
remains unclear.
The mtDNA deletions and mitochondrial energy
imbalances observed in progressive MS are probably
caused by mitochondrial oxidative damage and impaired
function of their respiratory chains, to which chronic
neuroinflammation, in part, contributes116. The result is
a hypoxia-like state that produces injury, similar to that
observed in stroke109. To date, the reason why the num­
ber of mitochondria increases in both active and inactive
lesions with a contrary global reduction in mitochon­
drial density in NAWM remains elusive. Lucchinetti
and colleagues117 hypothesized that mitochondrial
defects are involved in the development of hypoxia.
To investigate this hypothesis, the group analysed
pattern III MS lesions, which are found in patients with
fulminant MS and are defined by early loss of specific
myelin proteins and apoptosis of oligodendrocytes.
In these lesions, investigation of cytochrome c oxidase
— a major mitochondrial respiratory chain protein —
revealed a reduction in the immunoreactivity of one
subunit, complex IV109. The catalytic component of
complex IV, cytochrome c oxidase subunit 1 (COX1), as
shown by immunohistochemistry, is reduced in oligo­
dendrocytes, astrocytes and axons, but not microglia.
The authors postulated that the observed mitochon­
drial alterations could explain the damage to oligoden­
drocytes and axons that occurs during progression of
MS. Although the overall number of mitochondria is
increased, this theory might explain why energy imbal­
ance occurs in progressive MS. Indeed, damage to the
respiratory chain could be indirectly linked to neuronal
damage. In post-mortem studies in patients with pro­
gressive MS, the reduction in complex IV activity was
associated with axonal degeneration, as indicated by
the presence of non-phosphorylated neurofilament118.
Furthermore, the inhibition of complex IV leads to
increased glutamate-mediated axonal injury in vitro118.
These findings stress the importance of mitochon­
drial damage for the degenerative aspect of progressive
MS pathophysiology.
Mitochondrial damage is partly explained by the
aforementioned oxidative stress via immune cells, but
mitochondria themselves are also major producers
of ROS under homeostatic conditions. In addition to
mtDNA alterations, oxidative damage to DNA has been
found in RRMS and SPMS lesions, although in the lat­
ter damaged DNA is associated with a reduced level of
inflammation119. Oxidative stress can be evaluated by
measuring the expression of heat shock proteins such as
mitochondrial 70-kDa heat shock protein (mtHSP70),
a chaperone that is upregulated in cells during oxida­
tive stress120 and is involved in the folding and assembly
of mitochondrial proteins121. In MS lesions, mtHSP70
is upregulated in astrocytes and axons110. In EAE, over­
expression of mtHSP70 using gene therapy led to a
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major reduction in axonal damage, which was associated
with improved mitochondrial respirational activities (as
assessed by the activity of NADH cytochrome oxido­
reductase)121. The benefits of therapeutic restoration of
mtHSP70 under inflammatory conditions along with
the preponderance of oxidative stress in progressive
MS suggest that targeting mitochondrial function via
gene therapy could be a promising therapeutic avenue
in progressive MS.
Axonal damage and potential treatments
Mitochondrial damage is one of several factors linked
to axonal damage, which begins with focal swelling and
can later progress to transection and fragmentation
of the distal axon. In MS lesions, axonal transection is
detected and is a pathological correlate of irreversible
neurological impairment122. Axonal damage is an impor­
tant contributor to brain atrophy and is associated with
increasing disability in patients with progressive MS123.
Interestingly, a study of clinically silent MS lesions showed
a huge variability in axonal pathology. Some patients
had nearly complete axonal loss, whereas others had
nearly normal axonal density. However, the study
had the drawback that the lesion distribution was hetero­
geneous124. Damage to axons is found in acute demye­
linating plaques and also in inactive or remyelinating
lesions125. Axonal injury is associated with inflammation,
as shown by CD8+ T cell and macro­phage infiltrates
within lesions125. The presence of these inflammatory
cells suggests that axonal damage is mediated by inflam­
mation. Indeed, in animal models, axons can be injured
by application of ROS and RNS, which can be derived
from activated macrophages and microglia, independent
of demyelination53. In contrast to the situation in RRMS,
a small subset of slowly expanding lesions in progressive
MS show low-grade myelin and axonal destruction at
the white matter lesion margins with a substantially more
diffuse inflammatory reaction, comprising perivascular
cuffs of mononuclear cells, a diffuse infiltration of the
tissue by T cells and microglial activation14.
The disturbance of axonal transport of organelles
contributes to both axonal and mitochondrial damage.
Transport deficits even precede structural alterations
of axons, as shown in vivo with two-photon imaging in
MS models126. Importantly, the use of anti-inflammatory
interventions or redox-scavenging agents was able to
reverse these transport deficits. To our knowledge, this
approach has not been translated into clinical inves­
tigations. Taken together, ROS might damage axons
directly, but can also slow axonal transport, which results
in decreased mitochondrial densities in axons over a
long period of time, culminating in potential energetic
run-down.
Axons remove damaged mitochondria through
transport to the soma, where they are targeted for
mitophagy127. Mitochondrial transport along axons is
antagonized by anchoring proteins, such as syntaphilin
(SNPH), a neuron-specific mitochondrial protein. In
an animal model of progressive MS lacking compact
myelin, deletion of Snph led to a decrease in axonal
injury, reduced oxidative stress and improved mito­
chondrial health128. However, Snph deletion did not
beneficially alter clinical signs in a model of acute
EAE. The authors argue that anchoring of mitochon­
dria might have distinct effects during the acute phase,
in which anchored mitochondria produce increased
levels of ATP. During progression, the number of
damaged mitochondria increases, which, according to
the authors, might result in a maladaptive state with
the production of ROS and a perpetuation of damage.
Thus, inhibiting anchoring to improve mitophagy and
the transport of new mitochondria to the axon might
be a potential therapeutic approach. However, such a
treatment approach would be challenging and require
optimal timing.
Targeting ion channels
Progressive MS is associated with disturbances in ion
channels. To compensate for demyelination and per­
mit axonal conduction, denuded axons express an
increased number of sodium ion (Na+) channels along
the length of the axon129, which presumably increases
Na+ influx130. Myelinated axons from an optic nerve
isolated from a rat also produced a decrease in Na+/K+-
ATPase activity under anoxic conditions, resulting in a
collapse of the ionic gradient and Na+ influx via incom­
pletely inactivated Na+ channels131. At a certain thresh­
old, this elevated intra-axonal Na+ influx could reverse
the activity of the Na+/Ca2+ exchanger, leading to toxic
levels of Ca2+ influx. New studies using sodium MRI
support these mechanisms by demonstrating that Na+
levels are higher in the cortical grey matter, NAWM and
deep grey matter, as well as in T1 lesions, from patients
with SPMS than in those from patients with RRMS132.
These heightened axonal Na+ levels might be a corre­
late of axonal damage, as well as a mechanism driving
axonal injury in progressive MS. Thus, targeting Na+
channel alterations is considered a promising therapeu­
tic intervention, although data from clinical trials are
controversial (Fig. 1).
Phenytoin is a therapeutic agent that targets voltage-
gated Na+ channels. This agent was investigated in a
placebo-controlled phase II trial in 86 patients with
optic neuritis, in which measurement of retinal nerve
fibre layer (RNFL) thickness was the primary end
point133. In the trial, a 30% reduction in the loss of
RNFL thickness was found in the phenytoin-treated
group compared with the placebo group after 6 months,
supporting the neuroprotective effects of this approach.
Another Na+ channel blocker tested in progressive MS
is the anti-epileptic drug lamotrigine. Unfortunately, in
a randomized phase II trial that included 120 patients
with SPMS, lamotrigine (at a target dose of 400 mg
daily) failed to attenuate the loss of cerebral volume
relative to placebo over 24 months134. Interestingly,
patients treated with lamotrigine had an early loss in
partial (central) cerebral volume, white matter volume
and whole-brain volume compared with the placebo
group during the first 12 months, which was hypothe­
sized to be related to its anti-inflammatory properties.
However, this theory is still speculative. Importantly, no
decrease in grey matter volume occurred with lamo­
trigine treatment, and volume loss partially reversed
after stopping treatment. Of interest, lamotrigine
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treatment significantly reduced the deterioration of
the T25FW (P = 0.02) without an effect on other sec­
ondary outcome measures. As activated microglia and
macrophages exhibit increased expression of the Na+
channel Nav1.6 and as blockade of Na+ channels leads
to improved EAE outcomes135, lamotrigine treatment
in this trial might have dampened the inflammatory
response, which, paradoxically, might have decreased
brain volume. The potential benefits of lamotrigine
are, however, still probably due to its assumed mech­
anism of action. Indeed, early volume loss has been
reported with the use of immunomodulatory drugs in
patients with RRMS136 and can in part be explained by
fluid shifts137. These data speak to the complexities of
using morphometrics as a primary outcome measure
in a clinical trial, as it remains challenging to separate
pseudoatrophy related to fluid shifts from real atrophy.
Although lamotrigine failed in this trial, blocking Na+
channels might, nevertheless, be a promising approach.
Another approach to the prevention of Na+ and
Ca influx is by blocking the activity of acid-sensing
2+
ion channel 1 (ASIC1), which is permeable to Na+
and Ca2+. This approach is supported by preclinical
data, whereby Asic1-knockout mice have reduced
axonal degeneration following EAE138. Similarly, in
mice exhibiting chronic–relapsing EAE, treatment
with the ASIC1 antagonist amiloride was neuroprotec­
tive139. In samples from patients with progressive MS,
ASIC1 expression was associated with axonal damage
in chronic lesions140, suggesting that targeting this ion
channel could have neuroprotective effects. Indeed,
amiloride treatment markedly decreased brain atrophy
in the thalamus and also decreased corticospinal tract
atrophy in a small cohort of 14 patients with PPMS140.
Thus, targeting ASIC1 could be a promising approach
to the treatment of progressive MS. Currently, amiloride
is being investigated in the randomized, double-blind,
placebo-controlled ACTION trial in optic neuritis
(NCT01802489) and in the phase IIb MS-SMART
trial in patients with SPMS (NCT01910259; Table 1).
Pregabalin, a medication targeting voltage-dependent
Ca2+ channels, ameliorated clinical symptoms in EAE
models (when administered in both a prophylactic and
a therapeutic treatment paradigm) and reversed the
increase in neuronal intracellular Ca2+ levels in EAE
lesions141. Moreover, pregabalin improved myelin repair
in a model of lysolecithin-induced focal demyelination
concomitantly with improvement in visual evoked
potentials142. However, to our knowledge, no trials are
evaluating pregabalin in MS.
Modulating glutamate neurotransmission
Excess release of a specific neurotransmitter, glutamate,
is also observed in patients with progressive MS. At high
concentrations, glutamate increases intracellular calcium
levels by directly opening postsynaptic ion channels143
and, therefore, excess glutamate levels are thought to
be a source of neuronal injury in PPMS. Glutamate
concentrations are increased in the NAWM in patients
with early MS144, but decrease over time. Indeed, in an
MRI-based study, patients with SPMS had an annual
decrease of ~5% in the levels of glutamate and glutamine
Nature Reviews | Drug Discovery
Reviews
(an amino acid precursor for glutamate synthesis)145. The
authors argued that increased glutamate release during
early stages of MS could be followed by synapse dysfunc­
tion or loss, leading to reduced glutamate levels in pro­
gressive MS. Reducing early glutamatergic excitotoxicity
is, therefore, a promising approach to reduce disability
progression (Fig. 1).
Preclinical evidence supporting this approach
comes from blockade of the glutamatergic α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
and kai­nate (KA) receptors in EAE using the antago­
nist NBQX, which improved clinical scores146. Another
strategy to modulate glutamate neurotransmission is
by treatment with the amyotrophic lateral sclerosis
drug riluzole, an inhibitor of glutamate release147 and a
modulator of AMPA and KA receptors that increases
glutamate uptake 148. Riluzole reduces demyelina­
tion and axonal degeneration in EAE and leads to an
amelio­rated clinical disease course149. In small studies
in patients with PPMS, treatment with riluzole reduced
the rate of cervical cord atrophy and the development
of T1 hypointense lesions, but not the development of
new T2 lesions150,151. This finding might suggest a neuro­
protective effect of riluzole through the inhibition of glu­
tamatergic excitotoxicity. Currently, riluzole, amilo­ride
and the selective serotonin reuptake inhibitor (SSRI)
fluoxetine are being tested in patients with SPMS in the
phase IIb MS-SMART trial (NCT01910259; Table 1).
Unfortunately, preliminary results presented at the 2018
Congress of the European Committee for Treatment
and Research in Multiple Sclerosis (ECTRIMS) showed
no effect on percentage brain volume change in any
treatment arm152; final results are pending.
Treatment with the N-methyl-d-aspartate receptor
(NMDAR) antagonist amantadine also improved func­
tional outcomes in EAE models but had no effect on
the mRNA expression of the key glutamate transport­
ers GLT1 and GLAST, which were increased by ~200%
in EAE153. Another NMDAR antagonist, memantine
(used for the treatment of dementia), decreased glu­
tamate release and uptake, which was associated with
behavioural improvements in an EAE model153. Despite
the benefits of these NMDAR antagonists in preclini­
cal models, delayed administration resulted in synaptic
degeneration and mitochondrial abnormalities, indi­
cating that treatment should be administered early to
reduce potential glutamate-mediated damage to nerve
endings153. Memantine and amantadine also decreased
the production of the pro-inflammatory cytokines
IL-6, IL-1β and TNF in the brain154, and memantine
preserved axons in an acute optic neuritis model155,
demonstrating the general neuroprotective properties
of these medications. Memantine attenuated B cell
receptor (BCR) and Toll-like receptor 4 (TLR4) signal­
ling through blockade of the Kv1.3 and KCa3.1 potas­
sium channels, leading to enhanced production of the
anti-inflammatory cytokine IL-10 (ref.156). Thus, these
medications might also diminish the detrimental effects
of lymphocytes. Indeed, Kv1.3 channels have been pos­
tulated to be an interesting target for T cell activation,
as blockade of Kv1.3 channels in T cells has been shown
to reduce clinical signs in EAE157.
Reviews
Promoting remyelination
Demyelination is a key feature of MS that is present in
both grey and white matter structures. Although remye­
lination occurs, it is highly variable in patients with MS
and generally declines with age (for a review see ref.8).
As myelin is responsible for fast axonal conduction, its
loss leads to slowed or absent communication along
axons. Another key attribute of myelin, and the oligo­
dendrocytes that produce it, is that it provides a con­
duit for axonal support by glia158. One method by which
axons receive lactate, which can be used as a source of
energy, is through oligodendrocyte monocarboxylate
transporter 1 (MCT1). Disruption of MCT1 in oligo­
dendrocytes results in axonal degeneration, emphasiz­
ing the importance of oligodendrocyte health for axonal
degeneration independent of myelination159. A persistent
lack of myelin is thought to make axons more prone to
axonal degeneration. Indeed, when remyelination after
cuprizone-induced demyelination is prevented by irra­
diation, an increase in axonal loss occurs160, suggesting
that prolonged lack of myelin in MS accounts for axonal
drop-out. As remyelination might limit axonal degen­
eration in MS, promoting remyelination is a potential
therapeutic strategy for the treatment of progressive
MS8 (Fig. 1).
One of the biggest challenges for remyelination is
that the microenvironment in lesions contains a large
number of molecules that impair remyelination, such as
chondroitin sulfate proteoglycans (CSPGs)161, fibronec­
tin162 and netrin-1 (ref.163). Thus, as discussed else­
where8, the simultaneous targeting of several inhibitory
molecules may be necessary for remyelination.
LINGO1-targeted antibodies
Largely as a means to spare axons, remyelination-
promoting therapies are deemed to be the next fron­
tier in the treatment of MS. One exciting approach
is targeting leucine-rich repeat neuronal protein 1
(LINGO1), a negative regulator of oligodendrocyte dif­
ferentiation164. Indeed, antagonizing LINGO1 improved
remyelination and clinical signs in EAE models 165.
A phase I clinical trial showed that the LINGO1-
targeted antibody opicinumab (BIIB033) is safe and
well tolerated in healthy volunteers and patients with
MS166. In the phase II RENEW trial, which evaluated
the use of opicinumab (100 mg kg−1 intravenously every
4 weeks for six doses) in the treatment of optic neuritis,
the primary end point of improving the latency of visual
evoked potentials of the affected eye compared with
the non-affected eye167 was missed (mean difference
in the intention-to-treat population –3.5 ms; P = 0.33). In
addition, optical coherence tomography did not show
any improvement in retinal nerve thickness follow­
ing treatment with opicinumab. This finding might
have been partially due to the short treatment period,
since a trend towards improvement was observed after
32 weeks (mean difference in the intention-to-treat popu­
lation –6.1 ms; P = 0.071). The trial is being extended
(RENEWED; NCT02657915) to evaluate whether there
are positive effects after 2 years. A 2019 analysis of
vision-related functional scores (25-item National Eye
Institute Visual Functioning Questionnaire, 10-item
Neuro-Ophthalmic Supplement and high-contrast
visual acuity) in participants in the RENEW trial con­
cluded that there was no difference in mean change
from baseline at 24 weeks between the placebo and
opicinumab groups168.
Another phase II trial (SYNERGY) evaluating the use
of opicinumab (3, 10, 30 or 100 mg kg−1 intravenously
every 4 weeks up to week 72) versus placebo in the treat­
ment of relapsing MS was stopped by the sponsor as its
primary end point (proportion of participants confirmed
as positive responders for the primary multicomponent
end point) was missed; data have not yet been published.
However, as demonstrated in a platform presentation,
patients in the SYNERGY trial who received intermedi­
ate doses of opicinumab and had shorter disease dura­
tions might have benefited from the medication169. This
possibility could form the basis of future targeted clinical
trials investigating the effects of opicinumab treatment
on remyelination in patients with MS.
Elevating prolactin levels
Another possible approach to improving remyelina­
tion is by elevating levels of prolactin, a hormone that
induces remyelination170 and reduces disease severity
in EAE171. Pharmacologically, domperidone can be
used to induce prolactin production, and is currently
under investigation in a phase II clinical trial in SPMS
(NCT02308137; Table 1).
Biotin
High-dose biotin (MD1003) was investigated in a phase
III trial including 154 patients with progressive MS172.
After 12 months of treatment with either MD1003 or
placebo, all patients received MD1003 for 12 months.
The primary end point of improvement in EDSS scores
was achieved in 12.6% of MD1003-treated patients but
in none of the placebo-treated patients. Since biotin is
a cofactor for four carboxylases involved in fatty acid
synthesis, the authors proposed that the mechanism
involved in the beneficial effect of biotin was through
the promotion of remyelination172. Although the effect
size was small, high-dose biotin might be a promising
treatment approach. However, the long-term benefit of
MD1003 remains to be investigated. MD1003 is being
investigated in a phase III follow-up study in patients
with SPMS and PPMS, with EDSS and T25FW as the
primary end points (NCT02936037; Table 1).
Emerging remyelinating agents
Other drugs that promote remyelination are under active
investigation8, with several promising drugs for clinical
translation in progressive MS.
A screening approach investigating more than 1,000
compounds regarding their potential to improve remye­
lination showed that antimuscarinic medications have
strong remyelinating effects173. The most effective can­
didate in vitro was the first-generation antihistamine
clemastine. In addition, clemastine improved remyelina­
tion in the mouse model of cuprizone-induced demye­
lination173. These findings led to the initiation of two
clinical trials evaluating clemastine in MS: ReBUILD
(NCT02040298) and ReCOVER (NCT02521311).
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 Reviews

ReBUILD was a phase II randomized, double-blinded,
placebo-controlled crossover trial in 50 patients with
MS and chronic demyelinating optic neuropathy that
assessed improvement in visual evoked potentials174.
Clemastine therapy significantly improved laten­
cies by 1.7 ms (95% CI 0.5–2.9; P = 0.0048). However,
clemastine-treated patients reported more fatigue than
those in the placebo arm. To date, clemastine has not
been investigated in progressive MS.
Another remyelinating agent, the selective oestrogen
receptor modulator bazedoxifene, has been found to
enhance the differentiation of oligodendrocyte precursor
cells into oligodendrocytes and to promote remyelination
in an in vivo model of focal demyelination, presum­ably
functioning via 3β-hydroxysteroid-Δ8,Δ7-isomerase,
a key enzyme involved in the cholesterol biosynthesis
pathway175. Another screen using primary rat optic
nerve-derived progenitor cells identified benztropine,
an anticholinergic, which enhanced remyelination both
in vitro and in vivo176.
Conclusions
The pathological hallmarks of progressive MS dif­
fer from those of RRMS in their extent. In contrast to
RRMS, progressive MS is characterized by a greater
degree of atrophy resulting from chronic axonal loss,
impaired homeostasis of glia with production of ROS
and RNS, and mitochondrial damage with clonal expan­
sion of mtDNA deletions. Demyelination increases the
energy demand of axons. Impaired axonal transport
of organelles, especially mitochondria, contributes
to axonal dysfunction with altered metabolism and
disturbances of ion channels such as sodium chan­
nels. In addition, different immune cell types, such as
B and T lymphocytes, are involved in the perpetuation
of progression, for example, through the expansion of
B cell aggregates.
Targeting these pathophysiological processes is dif­
ficult owing to the diversity of mechanisms involved.
Additionally, available models incompletely mirror
the human situation and, therefore, preclinical test­
ing of treatment strategies remains challenging (Box 1).
Importantly, the complexity of pathophysiological
processes involved in progressive MS suggests that
targeting different processes simultaneously would
be a promising therapeutic approach. Thus, the ideal
future of progressive MS therapy would involve precise,
multi-dimensional therapeutic approaches, and would
probably involve combination therapies. As discussed in
this Review, a plethora of potential treatment approaches
are at different stages of development. However, prioriti­
zation of these therapeutic agents is currently difficult as
the most prominent pathophysio­logical processes driving
progression, which are the most crucial to target, remain
uncertain. Nonetheless, our opinion is that neuroinflam­
mation that is driven not only by microglia, astrocytes and
CNS-infiltrated macrophages, but also by B and T cells,
at least needs to be attenuated. In parallel, we believe that
neuro­protective and remyelination-promoting strategies
need to be introduced. Comorbid factors associated with
progression, including diabetes mellitus, hypertension
and smoking (which have been reviewed elsewhere177),
also need to be addressed therapeutically to reduce pro­
gression; however, their relative importance is probably
less than that of neuroinflammation-driven injury or the
need for strategies that promote neuroprotection and
remyelination.
In addition to selecting the best compounds for
future trials, trial design must be optimized (discussed
elsewhere178) as outcome parameters are heterogeneous
and often do not show treatment effects on disease pro­
gression. In conclusion, with the growing understanding
of the pathophysiology of progressive MS, the number of
treatment approaches targeting specific pathological
mechanisms has increased, raising hope for a bright
future for progressive MS therapy.
Published online xx xx xxxx

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Acknowledgements Related links
The authors acknowledge the many trainees and collabora- ClinicalTrials.gov: https://clinicaltrials.gov
tors who have contributed to our knowledge on multiple
www.nature.com/nrd