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Current treatments for multiple sclerosis usually focus on the ability to slow the progression of the disease. However, an incomplete understanding of the mechanisms of pathology reduces their effectiveness and limits the possibilities of treatment. The study, conducted at the University of Alberta (Canada), is one of the few studies of a neuroregenerative therapy strategy using, in particular, a molecule called fractalkine. In diseased mice, the latter would reverse the process of demyelination by renewing myelin-producing cells. This remyelination allows, in particular, to restore the fluidity of the neural connection. Thus, the molecule could potentially be used to treat other neurodegenerative diseases.
Multiple sclerosis, most often manifested by mild symptoms (at the beginning), is a demyelinating autoimmune disease that sometimes reaches the complete paralysis of patients. Gradually destroyed by the inflammation caused by the disease, the myelin sheath of neurons is no longer able to properly maintain the connection between nerve fibers. In other words, the disappearance of this sheath prevents the smooth circulation of nervous information.
On the other hand, you should be aware that the regeneration of oligodendrocytes, the only brain cells that can produce myelin, is especially inefficient in humans. These specific cells differentiate from the neural stem cells present in the brain. The aim of the new study, published in the journal Stem Cell Reports, is to validate a strategy to stimulate these neural stem cells to stimulate remyelination by generated oligodendrocytes.
“We have made a lot of progress in the medical and research communities on progression-altering therapies for multiple sclerosis, but what we don’t really have — an unmet need in the multiple sclerosis community — is regenerative therapies for the nervous system,” says Anastasia Voronova, assistant professor of medical genetics at the University of Alberta and co-author of the new study.
In a previous study, Voronova indeed demonstrated that fractalkine (or the chemokine CX3CL1) can stimulate the differentiation of neural stem cells into oligodendrocytes. Previously, this molecule was thought to play a role only in the immune system, specifically in the modulation of neuroinflammation. But Voronova’s research has shown that it may play a role in the remyelination process. “The molecule and its receptor work together to set off a signaling cascade within nerve cells,” she explained in a press release.
The main role of fractalkin in remyelination has now been confirmed in mice (as part of a new study). “If we can replace these lost or damaged oligodendrocytes, they can produce myelin, and it is believed that this will stop the progression of the disease and even reverse some of the symptoms,” the expert estimates.
Molecule tested on healthy and diseased mice
As part of their study, Canadian scientists injected fractalkine into mice, in which they chemically caused a disease that mimics multiple sclerosis. The treatment was then found to increase the number of new oligodendrocytes as well as reactivated progenitor cells in sick mice. Remyelination must have occurred in both the corpus callosum and the cortical gray matter. A decrease in neuroinflammation was also observed.
Namely, that during the study, the researchers had previously tested the safety of the treatment in healthy mice and observed similar effects (production of new oligodendrocytes). The next step was to determine how the molecule would act in mice that were induced with the disease, with the ultimate goal of clinical trials.
In addition, the researchers also demonstrated that in vitro activated oligodendrocytes and microglia (macrophages present in the central nervous system) express a specific fractalkine receptor. This receptor activation demonstrates the pro-regenerative role of fractalkine both in a sick mouse model and in isolated cell cultures.
As a next step, the researchers plan to test the molecule in other neurodegenerative diseases (in mice) associated with demyelination. The route of introduction of the new treatment will also be explored to overcome the known problem of the blood-brain barrier. Voronova’s team will study, in particular, the nasal spray route, which, according to other studies, seems promising.