Sclerosis (MS) is an autoimmune disease affecting the central nervous system(CNS).
It is characterized by autoreactive immune cells that induce demyelination and
neuronal degradation(1). There are three subtypes of MS based on
disease progression: relapsing-remitting MS (RRMS), secondary progressive MS
(SPMS), primary progressive MS (PPMS)(2). Current drug therapies,
which target the autoimmune aspect, have shown efficacy for RRMS but have
failed to help SPMS and PPMS(2-3). These autoimmune based therapies
can help prevent and slow down neural damage but cannot repair the lost myelin(4).
Re-myelination of neurons is the only way to restore the function that has been
lost and research to find therapies are currently underway(5).
When neurons in the CNS are injured
or damaged oligodendrocyte progenitor cells (OPCs), the myelin-producing cells
of the CNS, respond to the area. These cells would then mature and
differentiate into adult oligodendrocytes(2,5). In MS patients,
these OPCs are blocked from differentiating by changes in the local environment
such as extracellular matrix components brought in through vasculature leakage(5).
Myelination of axons enables fast, salutatory impulse propagation(4).
The myelin sheath creates a low capacitance environment allowing for increased
speed, decreased refractory periods, and more action potentials per unit of
time(6-7). Demyelinated axons can lead to motor, cognitive and
sensory impairments such as blurred vision, difficulty in controlling
movements, difficulty controlling bodily functions(2,4,7). If the
neural cell remains demyelinated it will try to overcome the short circuitry
which will lead to oxidative injury, energy failure, possible axonal injury,
glial scars and ultimately neuronal death(8-9). The continuation of
demyelination forms lesions and will cause brain atrophy, these can be markers
for the progression of MS in patients.
Current treatments for MS are based
on reducing inflammation and autoreactive immune attacks. These treatments are
successful at reducing the severity and frequency of relapses/attacks(5).
While multiple disease-modifying therapies have been approved for use in
patients with RRMS there is only one FDA approved therapy for patients with
PPMS, ocrelizumab(10). Although there are no current therapies for
direct re-myelination, some current therapies may be able to be used in
combination with future re-myelinating therapies. Mitoxantrone, an FDA approved
immunosuppressive therapy, has been shown to reduce axonal damage in severe
patients(3). Immunosuppressive drugs like mitoxantrone can reduce
neuronal degeneration and improve neuronal survival, which allows more time for
either natural based re-myelination or in the future for new therapies in
combination to help re-myelinate neural cells(5).
Since the local environment of
lesions is not conducive for OPC differentiate, stem cell transplantation
therapy is a viable option for further research. Donor neural precursor cells
were injected into mice and found in areas of damage, undergoing
re-myelination. The neural precursor cells also release platelet-derived growth
factor-AA and fibroblast growth factor-2 which can help signal endogenous OPCs
to proliferate and differentiate into mature oligodendrocytes which can also
help re-myelinate damaged neurons(2). Mesenchymal stem cells (MSCs)
are another potential stem cell therapy. MSCs were injected into mice and found
able to cross the blood-brain barrier and migrate to sites of demyelination.
MSCs have shown major improvement in re-myelination in mice but because they
are stem cells they pose a risk of differentiating into multiple cell types. To
avoid unwanted differentiation MSCs can be cultured in a neural progenitor
medium to create MSC-derived neural progenitors (M-NPs). When further research
was done to test the efficacy of M-NPs, researchers found that there was less
demyelination in the spinal cord, there was increased motor function and that
M-NPs express anti-T-cell properties because there was a lower concentration of
T-cells. With these results, the FDA approved Phase I clinical trials of M-NPs
being injected intrathecally into the cerebral spinal fluid(2,5). Another
form of stem cell therapy is hematopoietic stem cell transplantation. The
transplantation is following a high-dose immunosuppressive therapy, this
procedure in Phase II trials has sustained remission of active RRMS and shown
signs of regeneration. The combined therapy works by resetting the immune
system to self-antigens and eradicating autoreactive cells(9).
Antibodies which are part of the
autoreactive system that is targeting neurons and causing MS are another type
of therapy that is being explored. The Nogo-A co-receptor LINGO-1 is a
transmembrane protein expressed in neurons and oligodendrocytes where it is a
negative regulator of oligodendrocyte differentiation and consequently inhibits
myelination(2,5,8). Blocking this receptor would be a potential
therapeutic strategy for inducing OPC differentiation and re-myelination. The
animal model used to test these effects is called experimental autoimmune
encephalomyelitis (EAE), which is induced through injections(2). Through
successful trials of anti-LINGO-1 antibodies in mice induced with EAE, axons
increased their integrity and myelin sheaths began to form resulting in overall
axonal recovery(2,9). With success in animal models the antibody
BIIB033, which is an IgG1 monoclonal antibody, was created(2,5,8-9).
In Phase I trials in patients showed it was well tolerated and was unexpectedly
able to cross the blood-brain barrier through detectable concentrations in the
cerebral spinal fluid(2,8). The first Phase II trial was conducted
in patients with a first episode of optic neuritis, and after 24 weeks faster
impulse conduction was recorded along the optic nerve compared to the placebo
group, which shows myelin repair(5,8-9). A different Phase II trial
investigating the impact of disease progression in patients with RRMS and SSMS
was conducted(5,8-9). Another antibody, rHIgM22, which binds to
myelin and the surface of oligodendrocytes and prevents their death through
apoptosis is another possible therapy for patients with MS(2,5,8-9).
rHIgM22 was first tested as a treatment for Theiler’s murine encephalomyelitis
virus (TMEV) model of MS in mice(2). Although this antibody binds to
OPCs it is shown to inhibit differentiation and it is unknown how it still
promotes myelin repair(5). Treatment of rHIgM22 in TMEV model mice
showed a 64% decreased in lesion size compared to the control group(2).
The efficacy of this treatment was tested in Phase I clinical trials and with
success in the initial single dose therapy a second Phase I trial is underway
testing dose escalation(2,5,8).
Another study that shows a potential
therapy for MS is the use of high-dose biotin. Biotin is a water-soluble
vitamin, part of the B-complex family that acts as a cofactor for decarboxylase
enzymes(8-9). Biotin is a cofactor for two isoforms of acetyl-CoA
carboxylase (ACC1 and ACC2), ACC1 is a catalyst in the rate-limiting step in
the synthesis of fatty acids detectable in myelin(8). Through its
role in ACC1 biotin may possible treatment for promoting re-myelination by
increasing the fundamental building blocks needed for myelin sheath production(8).
In an open-label pilot study of biotin (100-300 mg/day) revealed improvement in
disease progression in patients with SPMS and PPMS that have optic neuropathy
and spinal cord injuries(8-9). The efficacy observed in this
open-label pilot study shows biotin is effective at reducing chronic disability
and in reversing disease progression(8). MD1003 is an oral form of
high-dose pharmaceutical-grade biotin in development for the treatment of PPMS(8).
A Phase III trial of a 300 mg daily dose of biotin is currently testing the
efficacy and safety of such a high dose(8). The results from both
studies showed that there was a delay in the time between the start of
treatment and the start of clinical improvement in patients. This may suggest
that biotin acts in some slow repair mechanism but currently does not provide
enough evidence for clinical treatment. There is more data to be collected from
the studies that may change the assessment of the drug viability(8).
One of the oldest anti-psychotic
drugs, lithium, is a potential therapy route to promote OPC differentiation,
proliferation, and increased myelin(9,11). Lithium is an inhibitor
of glycogen synthase kinase-3 (GSK-3), a serine-threonine protein kinase and also
has anti-inflammatory properties(9,11). Currently, lithium is used
to treat bipolar and depressive disorders, and there is growing evidence that
it exhibits neuroprotective and neurogenesis factors(11). The
inhibition of GSK-3 mimics the Wnt/beta-catenin signaling pathway, which is a
driver of myelin gene expression(11). In one study lithium chloride
(LiCl) was used to study the effect of re-myelination after myelin injuries(11).
LiCl was able to increase gene expression of myelin genes and decrease the g-ratio,
which is defined as the diameter of the axon divided by the diameter of the
axon plus myelin(2,11). One limitation of re-myelination is that
re-myelinated axons tend to have thinner myelin sheaths which means decreased
conduction of impulse signals(2). A lower g-ratio shows that the
axon has a thicker myelin sheath and is better for nerve cell function(2).
Although this study was testing the re-myelination of a peripheral facial
nerve, the researchers of the study believe that this information and strategy
can be applicable to the CNS and a possible treatment for MS(11). A
separate Phase I/II trial of progressive MS forms is currently underway(9).
Although this study is based on the idea of lithium as a regulator of
inflammation, disease severity will be measured and possible re-myelination
could be a potential outcome.
Pregnancy, a possible reducing agent
of disease activity in MS. Domperidone is a dopamine-2 receptor antagonist,
which can increase secretion of prolactin(9). Studies performed in
EAE models showed that prolactin can promote myelin repair and therefore is a
potential target for re-myelination therapy in patient with MS(9).
There is well-established data to show the disease reducing activity in MS that
occurs during pregnancy, likely due to the higher levels of prolactin secretion(9).
There is currently a Phase II trial of domperidone underway for patients with
Although current treatments for
re-myelination in patients with multiple sclerosis are absent there is great
potential for current research to solve this problem. There are many different
mechanisms by which therapies directed towards re-myelination can explore. Using
the body’s own re-myelination processes like stem cell and antibody therapies
is a current route of research. Also by discovering the pathways involved in
re-myelination and using drugs to target different steps like lithium chloride,
is another viable route in finding therapies for MS. Re-myelination therapies
alone will not be the most suitable form of treatment, in combination they
should also include anti-inflammatory and neuroprotective aspects as well. By
reducing the damage done by inflammation and the bodies self-reactive immune
cells is important alongside with neuroprotective factors to maintain neural
integrity as long as possible(1,5). This allows a greater window for
re-myelination and recovery from the symptoms of MS. Multiple sclerosis is a
complex, multifactorial disease that with future therapies is showing much
promise in the efficacy of treatments and hopefully one day a cure.