Multiple Sclerosis (MS) is an autoimmune disease that primarily affects women. It is characterized by oligodendrocyte death, leading to a loss of myelin, causing symptoms such as muscle weakness, neuropathy, numbness, and mood changes. The current etiology of MS is believed to be autoreactive T-cells and B-cells that cross the blood-brain barrier and release cytokines that damage and kill oligodendrocytes and subsequently the myelin. Oligodendrocytes maintain the myelin and support the axons, and myelin insulates axons and increases conduction speed, which are very important for a well-functioning nervous system. The majority of MS patients are diagnosed with the relapsing-remitting type, in which they have a flare-up causing demyelination and experience new symptoms, followed by a remission phase in which remyelination takes place. Remyelination is often incomplete, which is what Dr. Chen hopes to improve.
Dr. Yanan Chen’s research focuses on promoting myelination and helping oligodendrocytes endure inflammation in the central nervous system. She uses small molecule Sephin1 and the drug BZA in the presence of IFN-y, a cytokine released by T-cells, which causes widespread inflammation in the brain. Previous studies have shown that Sephin1 and BZA promote remyelination, but Dr. Chen proved they were still effective with active inflammation. Sephin1 prolongs the integrated stress response (ISR) by preventing GADD34 and PP1 from interacting so that they cannot dephosphorylate eIF2a. Phosphorylated eIF2a downregulates global protein translation and upregulates cytoprotective gene transcription. Downregulation of global protein translation gives the oligodendrocytes time to rest and recover, and also allows the mRNA to build up to form stress granules, which promote cell survival. BZA speeds up oligodendrocyte precursor cells to differentiate into mature oligodendrocytes. She used cuprizone to kill off oligodendrocytes and IFN-γ to induce inflammation in her experiments. She showed that the combined treatment of Sephin1 and BZA increased the number of myelinated axons and thickened the myelin.
Currently, there are no remyelinating drugs available to MS patients. However, both Sephin1 and BZA are presently in clinical trials. Sephin1, or IFB-088, is undergoing clinical trials by InFlectis Bioscience and is in phase 2a. It was safe in healthy volunteers and those with bulbar-onset amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease that results in the loss of motor neurons, leading to muscle weakness and paralysis. All ALS patients received riluzole, a known ALS drug, and they either were given a placebo or Sephin1. The Sephin1 group saw a statistically significantly slower decline, with a -0.95 monthly symptom point compared with the control’s -1.42. Interestingly, modulating the ISR pathway can treat many different nervous system diseases, not just MS! InFlectis Bioscience also suggests it could be useful in treating Charcot-Marie-Tooth disease. In addition, BZA is already FDA-approved, and its efficacy in promoting remyelination in MS patients is undergoing clinical trials at the University of California, San Francisco. Participants are female MS patients between the ages of 45 and 65, and the trial is set to conclude at the end of 2025. While no updates have been released, many community members look forward to the results. If Sephin1 and BZA become approved treatments for MS, hopefully, researchers will conduct clinical trials to test their efficacy together.
Dr. Chen’s research shows promising results for using BZA and Sephin1 to promote remyelination and confer protection of oligodendrocytes in an inflammatory environment. With clinical trials underway, these treatments can hopefully slow neurodegeneration and enhance myelin restoration. In addition, they can inspire further studies to research whether they could be effective treatments for other neurodegenerative diseases. The next stage of clinical trials will be critical in determining whether BZA and Sephin1 can improve the quality of life for MS patients.
Chen, Yanan, et al. “Insights into the Mechanism of Oligodendrocyte Protection and Remyelination Enhancement by the Integrated Stress Response.” Glia, vol. 71, no. 9, Sept. 2023, pp. 2180–95. PubMed Central, https://doi.org/10.1002/glia.24386.
Inflectis - InFlectis BioScience Announces Promising Results for IFB-088 in a Phase 2a Clinical Study in Bulbar-Onset ALS Patients. https://inflectisbioscience.reportablenews.com/pr/inflectis-positive-prelim-results-of-ifb-088-in-ph2-study.
Nylander, Alyssa, et al. “Re-WRAP (Remyelination for Women at Risk of Axonal Loss and Progression): A Phase II Randomized Placebo-Controlled Delayed-Start Trial of Bazedoxifene for Myelin Repair in Multiple Sclerosis.” Contemporary Clinical Trials, vol. 134, Nov. 2023, p. 107333. PubMed, https://doi.org/10.1016/j.cct.2023.107333.
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