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Small molecule promotes myelin sheath repair in MS mice: Study
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A small molecule called ESI1 stimulated the repair of the myelin
sheath, the fatty coating on nerve fibers that is damaged in multiple
sclerosis (MS), a study found.
In an MS mouse model, this resulted in improved motor function and
nerve cell communication, as well as reduced signs of disease-driving
inflammation. ESI1 also enhanced myelin repair in aged healthy mice
while reversing cognitive decline.
"Currently, there are no effective therapies to reverse myelin damage
in devastating demyelinating diseases such as MS," lead author Q.
Richard Lu, PhD, scientific director at the Cincinnati Children's
Hospital Medical Center's Brain Tumor Center, said in a hospital press
release. "These findings are significant as they offer new pathways
for treatment that potentially shift the therapeutic focus from just
managing symptoms to actively promoting repair and regeneration of
myelin."
The study, "Small-molecule-induced epigenetic rejuvenation promotes
SREBP condensation and overcomes barriers to CNS myelin regeneration,"
was published in the journal _Cell_.
The myelin sheath is a fatty protective layer that forms around nerve
fibers in the central nervous system (CNS), which comprises the brain
and spinal cord. Produced by neighboring cells called
oligodendrocytes, it helps to speed up the transmission of electrical
impulses along nerve fibers. In MS, immune-mediated damage to the
myelin sheath (demyelination) impairs nerve function and
communication, which gives rise to MS symptoms.
### Understanding barriers to myelin sheath repair
Evidence suggests that, in areas of myelin damage, the ability of
oligodendrocytes to repair the myelin sheath (remyelination) is
impaired. Although defects in the growth of oligodendrocyte precursor
cells were thought to be the cause, recent data indicate that mature
cells also fail to properly remyelinate nerve fibers in MS lesions.
"The molecular barriers that prevent [oligodendrocytes] from producing
myelin are poorly understood, and no effective treatments are
available that reverse myelin damage or promote remyelination," Lu and
his colleagues wrote.
To better understand those barriers, the team first examined
oligodendrocyte function in post-mortem tissue samples from MS
patients with both active and inactive demyelinated lesions. While
levels of mature oligodendrocytes in MS lesions were comparable to
healthy brain regions, the cells inside lesions were epigenetically
silenced.
Epigenetics refers to cellular processes that control the activation
or deactivation of gene expression without altering a gene's DNA
sequence. Here, epigenetic silencing, or suppression of gene activity,
was found to be the barrier that prevented oligodendrocytes from
remyelinating nerve fibers in MS lesions.
After screening a library of compounds to find those that block
enzymes involved in epigenetic silencing, ESI1 (epigenetic-silencing-
inhibitor-1) was identified as the most potent, boosting myelin
production by about five times compared with the second-strongest
compound.
When demyelination was induced in mice, ESI1 promoted remyelination
and increased myelin thickness when the myelin repair processes had
already begun. ESI1 also enabled the production of new myelin on
regenerated nerve fibers following induced nerve damage.
ESI1 was then evaluated in a well-characterized MS mouse model called
experimental autoimmune encephalomyelitis, or EAE, which, like in MS
patients, has immune-mediated damage to the myelin sheath. Without
treatment, EAE mice developed chronic hindlimb paralysis, but disease
severity was markedly lower in ESI1-treated EAE mice.
In the lower spinal cord, the area most affected in EAE mice,
ESI1-treated animals showed more signs of remyelination and less
inflammation than controls, "suggesting that ESI1 may have an
immunomodulatory activity," the researchers wrote.
In line with these findings, ESI1 significantly improved motor
function and nerve cell communication in EAE mice.
ESI1 also boosted myelination in healthy-aged mice, slowed age-related
cognitive decline, and stimulated remyelination following
demyelinating injury.
To explore ES1's potential effectiveness in MS patients, the team
tested ESI1 in lab-grown brain organoids, which contain cells arranged
in a three-dimensional architecture that resembles the human nervous
system. Here, ESI1 promoted the activity of genes associated with
myelin generation and stimulated myelin sheath extension.
Mechanism-of-action experiments demonstrated that ESI1 triggered
remyelination by blocking the activity of an enzyme called HDAC3, a
known epigenetic suppressor of gene expression.
But independent of HDAC3 inhibition, the compound also exerted its
function by activating SREBP1a and SREBP2, proteins that drive the
production of fatty acids and cholesterol in oligodendrocytes, the
main components of the fatty myelin sheath. "Our study highlights the
potential of targeting epigenetic silencing to enable CNS myelin
regeneration in demyelinating diseases and aging," the researchers
wrote.
"This study is a beginning," Lu said. "Prior to finding ESI1, most
scientists believed that remyelination failure in MS was due to the
stalled development of precursors. Now we show a proof of concept that
reversing the silencing activity in [oligodendrocytes] present in the
damaged brain can enable myelin regeneration."
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