Way Seen to Counter Blood-clotting Molecule That Blocks Myelin Repair
Blocking a particular receptor protein of the BMP signaling pathway effectively promoted the maturation of myelin-producing cells and myelin repair in two mouse models of multiple sclerosis (MS), a study showed.
Notably, these benefits, observed even after disease onset, took place in the presence of fibrinogen, a blood clotting factor that leaks into the brains of MS patients and acts as a myelin-repair blocker.
These findings support the use of BMP signaling suppressors — some of which are already in clinical testing for other indications — to eliminate fibrinogen-induced brakes in myelin repair (remyelination), which could slow MS progression.
“We found a new line of drugs that could potentially be used to stimulate myelin repair even in the presence of toxic blood leaks in the brain,” Katerina Akassoglou, PhD, the study’s senior author and director of the Center for Neurovascular Brain Immunology at Gladstone Institutes, said in a press release. Akassoglou is also a professor of neurology at University of California, San Francisco (UCSF).
The study, “BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis,” was published in the journal Brain.
Myelin, the protective sheath around nerve fibers that helps to speed transmission of signals between nerve cells, is damaged and lost in MS.
Myelin damage in the brain attracts immature, stem-like cells called oligodendrocyte precursor cells (OPCs) to lesion sites, where they mature into oligodendrocytes — myelin-producing cells capable of restoring the myelin sheath.
Despite the presence of OPCs in MS lesions, however, remyelination is incomplete or absent. As such, efforts are increasingly focused on identifying treatment approaches that promote oligodendrocyte maturation and remyelination.
While many such potential therapies have shown promise in lab-grown cells, these experiments generally do not take into account the toxic elements that naturally surround cells in an “MS environment.” Their absence can limit treatment efficacy when tested in clinical trials.
Akassoglou and her team, along with colleagues at University of California San Diego and the University of Vienna, in Austria, focused on the anti-remyelinating effects of fibrinogen, one of such toxic environmental cues, and identified a way to overcome it.
Fibrinogen’s leakage from blood vessels and its deposition near brain lesions “is one of the earliest events in multiple sclerosis … and persists in chronically demyelinated lesions but is minimal in remyelinated lesions,” the researchers wrote.
In a previous study, Akassoglou’s team showed that fibrinogen, a blood clotting factor, could also work as a signaling molecule and suppress oligodendrocyte development. Importantly, suppressing fibrinogen signals in lab-grown cells and mouse models of MS was found to promote remyelination.
Now, using an advanced microscopy technique that allows researchers to track cells and myelin structure in real-time inside a living mouse’s spinal cord, the team found that OPCs cluster at sites of blood leaks in the brain, and the presence of fibrinogen at those sites changes their fate.
Fibrinogen blocks myelin production “by causing a chain of events that prevents [OPCs] from transforming into myelin producers, forcing them instead to turn into cells that can make scar tissue,” said Reshmi Tognatta, PhD, one of the study’s co-first authors and a scientist in Akassoglou’s lab.
This OPC switch toward astrocytes, a cell type that can promote scarring, was found to involve the activation of BMP signaling receptor proteins.
The team then developed a screening assay to identify molecules that could promote oligodendrocyte maturation and myelin production in the presence of fibrinogen, mimicking the anti-myelin repair environment around OPCs that exists in MS.
“We can now screen, in a single assay, the efficacy of drugs to put the cells back on track for myelin repair,” Akassoglou said, adding that the new method “is ideal for the discovery of [therapies] that overcome the toxic lesion environment.”
Seven compounds previously known to promote oligodendrocyte maturation were unable to do so in the presence of fibrinogen. These included benztropine, Tavist (clemastine), quetiapine, miconazole, clobetasol, U-50488, and XAV-939.
“None of the drugs we tested could reverse the effect of fibrinogen,” said Mark Petersen, MD, the study’s other co-first author, a visiting scientist in Akassoglou’s lab, and an associate professor of neonatology at UCSF.
Among other screened compounds, the researchers identified a small molecule, LDN-212854, that could not only promote OPCs maturation into oligodendrocytes, but also stop their transformation into scar-producing cells due to fibrinogen.
LDN-212854 works by blocking the activity of a protein receptor of the BMP signaling pathway, called activin A receptor type I (ACVR1).
Notably, combining LDN-212854 with clemastine resulted in even greater increases in oligodendrocyte numbers, suggesting that this BMP suppressor could be combined with other pro-myelination agents for treating MS.
Treating two different MS mouse models with LDN-212854 increased myelin production and slowed disease progression, effectively preventing paralysis in these animals.
“This compound completely overcame the effect of fibrinogen and restored myelin repair around leaky blood vessels,” Petersen said, adding that “even if the treatment started after they were already sick, the mice improved and we saw signs that the myelin was repairing faster and there was less damage to their nervous system.”
“Our study identifies LDN-212854 as a selective ACVR1 inhibitor to overcome fibrinogen-induced BMP signaling in OPCs to promote remyelination,” the researchers wrote. “LDN-212854 increased myelinating oligodendrocytes and eliminated OPC differentiation to astrocytes in the presence of fibrinogen.”
Given that BMP signaling regulates immune functions, “we cannot exclude the anti-inflammatory effects of ACVR1 inhibition by LDN-212854 in addition to its promyelinating effect on OPCs,” the team added.
Other ACVR1 suppressors are currently being tested in clinical trials for other disorders, and so far appear to be safe. These compounds could potentially be repurposed and tested in MS patients much sooner than a new therapy might be developed, as that is an extensive process.
Petersen also noted that “the disruption of blood vessels and deposits of fibrinogen link many neurological diseases, from multiple sclerosis to neonatal brain injury — so a discovery in one area gives us a lot of insight into other disease processes.”
“We discovered that fibrinogen gains access to the diseased brain, acting as a gas pedal for toxic inflammation and as a break for repair,” Akassoglou concluded. “We are continuing to investigate its deleterious effects in the brain in hopes that we can develop effective therapies for multiple sclerosis and other devastating neurological diseases.”
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