Prolonging a cellular defense mechanism shown to restore myelin — the protective sheath around nerve cell fibers that is lost in multiple sclerosis (MS) — may be key to treating the neurodegenerative disease, a study in MS mouse models suggests.
That defense mechanism, called integrated stress response (ISR), helps protect both mature and newly formed oligodendrocytes, or myelin-producing cells, from the damaging inflammatory environment that characterizes brain lesions in MS.
The researchers said that “ISR enhancement may provide reparative benefit to MS patients” by increasing myelin thickness.
“Prolonging the integrated stress response helps the cells withstand the adverse inflammatory environment and gives the cells more time to recover,” Yanan Chen, MD, PhD, the study’s lead author at the Northwestern University Feinberg School of Medicine, said in a university press release.
In addition, combining this approach — achieved with a small molecule called Sephin1 — with bazedoxifene, an investigational therapy shown to promote oligodendrocyte maturation, resulted in the restoration of the myelin sheath to pre-lesion levels.
These findings highlight the therapeutic potential of ISR-promoting interventions, alone and in combination with myelin repair-promoting treatments, in MS, the team noted.
The study, “Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment,” was published in the journal eLife.
In the brain, myelin damage attracts immature, stem-like cells called oligodendrocyte precursor cells (OPCs) to the lesion site, where they mature into oligodendrocytes — myelin-producing cells capable of restoring the myelin sheath.
Despite the presence of OPCs in MS lesions, remyelination (myelin repair) is incomplete or absent. Notably, the complex inflammatory environment present in MS lesions is “considered a major contributor to impaired remyelination,” the researchers wrote.
While several molecules have been shown to promote oligodendrocyte maturation and/or remyelination in preclinical models, most of these models involve non-inflammatory myelin loss, failing to closely mimic what happens in MS.
“The inflammatory environment [in MS] is far from ideal for the repair process; there are debris from previously present myelin, infiltrating [immune cells] and myriad proinflammatory [molecules] not normally present in the brain,” said Brian Popko, PhD, the study’s senior author.
“In purified cells and some demyelination [myelin loss] mouse models, none of that is present,” added Popko, also the scientific director of the division of MS and neuroimmunology and a professor of neurology at the Feinberg School of Medicine.
As such, according to the researchers, “a remyelination model with an inflammatory environment would provide a better indication of the potential of remyelinating-promoting compounds for MS treatment.”
Using an inflammatory MS mouse model, called experimental autoimmune encephalomyelitis, or EAE, Popko and his team had previously shown that prolonging the integrated stress response — which is activated by harmful “insults,” or aggravating factors, including inflammation — protected mature oligodendrocytes from death, reduced myelin loss, and delayed disease onset.
This prolonged response was achieved with the suppression of GADD34, a key protein for terminating ISR. That was done either through genetic deletion or by treating the mice with Sephin1, a small molecule known to selectively block GADD34.
Moreover, combining Sephin1 with interferon-beta, an anti-inflammatory MS therapy, produced superior benefits than the therapies achieved when given separately.
Now, the team evaluated whether prolonging this natural response also protected newly generated myelin-producing oligodendrocytes and increased remyelination at the peak of myelin and oligodendrocyte loss.
The experiments were conducted in EAE mice and in a mouse model that closely mimics the inflammatory environment of the MS brain. That model allows for better control of the demyelination and remyelination processes.
The results showed that GADD34 genetic deficiency and Sephin1 treatment at the peak of disease both promoted repopulation of myelin-repairing oligodendrocytes and increased the number of remyelinated nerve fibers in these mouse models.
Notably, these effects were not observed in the absence of inflammation and were not associated with higher numbers of OPCs.
“Therefore, it is likely that the benefits of ISR enhancement on remyelination in the presence of inflammation are primarily due to the protection of actively myelinating oligodendrocytes,” the researchers wrote.
“Protection is better than having to repair, but either way you have to replace the oligodendrocytes that are lost,” Popko said, noting that Sephin1 “protects mature cells and the new cells that are necessary to replace cells that are lost.”
Sephin1 could be a potential treatment “because not only have we shown that it provides protection to oligodendrocytes against inflammation, but we now are showing that it promotes myelin repair in an inflammatory environment,” he added.
The team then tested the hypothesis that the efficacy of a remyelination-promoting molecule in an inflammatory environment would be boosted if combined with an ISR-promoting molecule.
Combining bazedoxifene, a molecule previously shown to boost oligodendrocyte maturation and myelin repair, with Sephin1 led to similar effects in oligodendrocyte survival and number of remyelinated nerve fibers to those observed with either therapy.
However, the combination treatment was significantly superior at promoting myelin repair, as myelin sheath thickness of remyelinated axons was found to reach pre-lesion levels in these mice.
Of note, bazedoxifene is approved in the U.S. in combination with estrogen for the treatment of menopausal symptoms, and is currently being tested as a remyelinating agent in a Phase 2 trial called ReWRAP (NCT04002934) of post-menopausal women with relapsing-remitting MS. The study may still be recruiting; more information can be found here.
“Combining current and previous findings, we believe that Sephin1 or similar ISR enhancing strategies will likely provide significant therapeutic benefit to MS patients when combined with current immunosuppressive treatment,” the researchers concluded.
Popko’s team plans to continue investigating the benefits of prolonging the integrated stress response in MS and is currently exploring opportunities for clinical trials.
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