Is Myelin Repair Possible?

 When you plug in a light, the bulb lights up in seconds. Everyday tasks like turning on a light happen so fast and work so effectively that we often take them for granted. You probably don’t stop to think about the impulse traveling from the outlet, through the cord, to the bulb, or the parts of the system that make this possible. The plastic coating on the wire helps the signal travel fast and efficiently, ensuring that the wires inside do not get damaged and that the electricity reaches its destination quickly. If the wire didn’t have a coating or if the coating got damaged, the light might get dimmer over time, or occasionally not turn on at all. In the body, myelin is the coating over the axons, the “wires'' carrying our body’s signals. The insulator around the wires acts the same way myelin acts as an insulator in the brain. The signals in the neurons of people diagnosed with multiple sclerosis (MS) become slowed and unprotected as their axons lose the coating that protects them. MS is an incurable demyelinating disease, where patients can experience weakened motor function, pain, impaired memory and other cognitive issues. MS patients endure such degeneration because their central nervous system cells lose the ability to communicate quickly. However, scientists may have discovered a drug that allows myelin production regardless of the presence of toxic proteins; this article will investigate the neuroscience behind Tolebrutinib as well as its results and limitations.

In MS, the immune system attacks the myelin sheath: an insulating layer of fat produced by glial cells known as oligodendrocytes that cover nerves and increase the speed of electrical impulses. Now, what does all of this mean? Let’s break it down. The brain consists of two types of tissues: white matter and gray matter. Gray matter contains unmyelinated parts of the neuron, and is mostly composed of cell bodies. White matter, on the other hand, consists of myelin-coated axons, the part of the neuron that sends signals to other neurons [1]. This myelinated white matter is critical for the relay of nerve impulses. Myelin itself allows for fast transduction of signals from across the body to the brain, so that the brain can respond.With MS, the immune system attacks the oligodendrocytes that produce the myelin sheath, leading to cognitive and motor dysfunction. Now you might be asking, why is damage to the myelin sheaths such a major issue? Deteriorated myelin cannot be repaired, and this breakdown can lead to leaks in the blood-brain barrier. This is extremely dangerous because the blood-brain barrier is a membrane that decides what in the blood can reach the brain and what cannot. Leaks, due to damaged myelin, result in toxins of the blood reaching the brain. One such toxin is a harmful protein known as fibrinogen [2]. Fibrinogen is a protein present in MS patients that causes blood clots. When this protein enters the brain it can block myelin repair, causing neuron loss, and neuroinflammation. Fibrinogen-driven clots can actually be used as diagnostic criteria in MS since they are visible in the brain and spinal cord during MRI scans [2]. Fibrinogen was a factor unable to be replicated in cultured drug trials.

In previous clinical trials, drugs intended to repair the myelin sheath have not passed initial stages because dangerous brain bleeds were one of the side effects. However, there is a new ray of hope for those suffering with MS. Katerina Akassologlou, PhD, the director of Center for Neurovascular Brain Immunology at Gladstone, and her team of scientists are collaborating with UC San Diego and University of Vienna on clinical trials of a new drug [3].The team has discovered a way to stimulate the production of myelin without causing bleeds and scarring. They accomplished this by screening their new drug in the presence of fibrinogen while mimicking the inhibitory environment among the repair cells [3]. This technique was designed to test the production of new myelin as well as the genesis of toxic and damaging cells present in the brain. Their drug contained a genetically engineered molecule that allowed for the damaged repair cells to transform into myelin-producing oligodendrocytes. Moreover, this technique involving their new molecule enabled myelin production and prevented paralysis in mice- eliminating one of the detrimental side effects of MS [3].

The goal of these clinical trials was to increase the formation of oligodendrocytes, thereby increasing the production of myelin. However, the novel finding has potential setbacks, because of toxic by-products produced by the immune system of those with MS, which hinders myelin repair. Drug trials were performed on cultured cells, in an in vitro study. This method allows researchers to control for outside forces, confounds, in their testing and isolate the neuronal cells and effects they’re looking for. However, testing these drugs in vitro may lack translational application. As the cells are isolated, the trials do not account for toxic elements like fibrinogen that exist in the cell’s environment.

These circumstances raise questions regarding the efficacy of any myelin repairing drug in the human brain. Yet, despite potential setbacks, it is plausible that scientists may have found a way for myelin to rebuild itself safely and effectively in the brains of those suffering with MS with this new line of drugs [2].

To determine just how harmful fibrinogen is in the brain and how it can be overcome, Akassologlou collaborated with Mark H. Ellisman, PhD, director of the National Center for Microscopy and Imaging Research (NCMIR) at UC San Diego. The outcome of this collaboration resulted in their teams developing a breakthrough microscopy technique involving  in vivo two-photon microscopy. The technique enabled the researchers to merge advanced 3D imaging and the high power capabilities of electron microscopy using a light optic-based imaging system that showed the spinal cord of a living mouse [2].

This microscopy technique allowed the researchers to view blood-brain barrier leaks, follow repair cells (cells that are able to regenerate others based on needs of the body), and track the already present myelin structures in real time, explains Reshmi Tognatta, PhD [3]. The technique advances current imaging methods because the effects of MS can be seen as they develop, which is impossible to do with a single scan. Oligodendrocytes work with astrocytes, the glial cells that control the blood-brain barrier and its flow. The imaging would allow for the viewing of the deteriorated myelin and the attempts to repair the blood-brain barrier. Tognatta was one of the initial authors of this study and was feeling particularly hopeful with this new microscopy technique. Upon imaging the mouse, the researchers were able to establish that repair cells rushed to the site of blood leaks and began to cluster where fibrinogen was present. Ultimately, they discovered that these cells were not revolutionizing myelin production as they had predicted, but rather fabricating scar tissue, acting as astrocytes [3].

These studies gave the researchers insight into the fibrinogen pathway. First, fibrinogen blocks myelin production, preventing repair cells from morphing into myelin producers at all. Since these cells were not producing myelin, they were then forming scar tissue, Tognatta explained.  Thus one of the major issues with fibrinogen is that this protein derails cell fate, halting the production of myelin [2].  

The collaboration of scientists then had one goal: to test if their new drug had the ability to overcome the harmful effects produced by fibrinogen [2]. They found that with this new drug, repair cells are able to fulfill their duty of repairing myelin while overcoming the toxic environment of the cell. These trials were carried out by establishing a new screening method to monitor the drugs when in the presence of fibrinogen. This new technique allowed the team of scientists to test the production of new myelin as well as the genesis of the destructive cells present in brain lesions.  

The new drug was successful in increasing the repair of myelin in a non-fibrinogen environment, similar to that of someone who does not have MS - but was deemed ineffective in an environment where fibrinogen was present, similar to that of someone who does have MS. They found that reversing the harmful effects of fibrinogen in these trials was going to be much harder than they had anticipated [2].

After their first unsuccessful attempt, alternative compounds were tested by the team in order to evaluate if any of them were able to increase myelin production with fibrinogen present. The discovery of a small molecule changed the trajectory of their entire clinical trial, and could prove to be revolutionary. The name of this compound is Tolebrutinib (C26H25N5O3) and it is able to pass through the blood-brain barrier to block the activity of cells that worsen MS [4]. This small molecule enabled repair cells to transform into oligodendrocytes instead of scar-producing astrocytes, even in the presence of fibrinogen. Upon lab testing on mice, they found that the mouse with MS who was prescribed the new compound had an increased production of myelin in the white matter of its brain and was saved from paralysis.

They found that even if the compound was administered to the mice after they were infected, the repair of myelin was increasing in speed and the harm to their nervous system was reduced [2]. The most important discovery of these trials was that this compound was able to completely overcome the harmful effects of fibrinogen while rebuilding myelin around leaky blood vessels: something that was thought to be extremely difficult, almost impossible, to accomplish.

After extensive testing, the new drug seems to be effective, though it must go through a long line of developmental processing and clinical trials to be deemed acceptable as a treatment. Similar compounds have been created by research groups proving that this new drug is able to be replicated, repurposed, and tested in MS clinical trials. Though there is still much work to be done, this development is a ray of hope for those suffering with MS.

Looking beyond multiple sclerosis, the myelin-enhancing molecule used in the new drug can be synthesized with various other drugs to repair myelin even more efficiently. This new finding has the potential to help a considerably larger group of people suffering from other demyelinating diseases. Peterson [2] explained,  “A discovery in one area gives us a lot of insight into other disease processes” which shows that this finding can aid in research of many other diseases. Furthermore, the molecule equips clinicians with a new option in their research to boost myelin production in the toxic leaky blood-brain barrier environment seen in multiple sclerosis. Akassoglou explains the importance of acknowledging blood leaks in diseased brains, and the implications that this research will have in the development of beneficial treatment designs for demyelinating diseases. Their discovery has shown that fibrinogen infiltrates the diseased brain and increases toxic inflammation, halting repair entirely [2]. The team is continuing to research fibrinogen deeper in order to create effective therapies for those suffering with MS and other devastating demyelinating diseases.  

The world of neuroscience is truly remarkable, as demonstrated by Akassoglou and her team of scientists. This study has opened the door to a world full of clinical opportunities; it is the pioneering work in developing cures to diseases such as MS. Though this new drug is not the cure to MS, it is a stepping stone that could lead to a breakthrough cure in the future. From coated wires on lamp chords to oligodendrocytes, myelin, astrocytes, and fibrinogen, we can see how important it is for impulses to travel quickly to ensure everything is running smoothly. With this new drug, the “lights” of those suffering with MS could shine much brighter for much longer.

References:

[1]. Ghasemi N, Razavi S, Nikzad E. Cell J. 2017 Apr-Jun; 19(1): 1–10. Published online 2016 Dec 21. doi: 10.22074/cellj.2016.4867 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241505/

[2]. Petersen MA, Tognatta R, Meyer-Franke A, et al. BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis. Brain. 2021;(awab106). doi: 10.1093/brain/awab106

[3]. Langelier, J. (2021, August 24). Overcoming Obstacles to Promote Repair in Multiple Sclerosis. The Gladstone Institute. https://gladstone.org/news/overcoming-obstacles-promote-repair-multiple-sclerosis

[4]. National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 124111565, Tolebrutinib. Retrieved January 10, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Tolebrutinib.