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Novel CNS Protection Strategies Compared to Disease Modifying Treatments in Multiple Sclerosis:

Kevin Kaschke

    Multiple sclerosis (MS) is an immune modulate death of oligodendrocytes leading to demyelination and eventually axonal death. The hallmark of the disease is inflammation and accumulation of myelin debris. Currently the treatments used are called disease modifying treatments (DMTs) that act similarly to chemotherapy in suppressing the adaptive immune system. DMTs work on the different T-cells active in the auto immune pathogenesis of MS. (1) The issue with DMTs is they are working at the peripheral immune system in an attempt to protect against the T-cell infiltration into the central nervous system (CNS). Current and new research is suggesting alternatives through CNS protection of oligodendrocytes. Two novel approaches have recently been pre-clinically discovered, Sephin1/BZA co-treatment by Dr. Chen (2) and small molecules that mediate GluA2 receptors reducing excitotoxicity by Dr. Fang Liu (3).

     Dr. Chen’s work was focused on using the GADD34/PP1 interaction inhibitor Sephin1 to prolong the integrated stress response (ISR) allow for transcription of cytoprotective genes and inhibition of global transcription. (2) It showed promising results in the number of oligodendrocytes and percent of axons myelinated, even in the high inflammation enviroment induced by the experimental MS model experimental autoimmune encephalomyelitis (EAE). Furthermore, Dr. Chen using adoptive transfer EAE, she was able to show Sephin1 indeed acts on the T-cells indirectly through CNS modulation. This was critical because it sets Sephin1 apart from all other DMTs in the fact the T-cell infiltration still happens, but the CNS can protect itself. The problem is even with co-treatment it only delays onset of the disease, not overall clinical scores. Finally, she investigated the selective estrogen receptor modulator Bazedoxifene (BZA) that previously has been shown to mediate oligodendrocyte precursor cells (OPCs) to mature oligodendrocytes. (2) Using a cuprizone demyelination and remyelination model with a double transgenic mouse to promote inflammation, she was able to test Sephin1/BZA co-treatment and found that it had no greater effect on any previously mentioned markers besides a lower g-ratio. Lower g-ratio means thicker myelin, promoting the idea that BZA keeps the existing oligodendrocytes alive and promotes more remyelination. Even with the large successes of Sephin1 co-treatment, the end stage of the disease needs to be reduced to have overall clinical effects.

     In an entirely different mechanism Dr. Fang Liu investigated mediating excitotoxicity from glutamate in the EAE MS model by designing drugs that bind to the allosteric site of the GluA2 subunit of the AMPA receptor (AMPAR). (3) This is much different than Dr. Chen’s work on a stress induced pathway, it focuses on the global AMPAR, and directly targets lesion areas. Using artificial intelligence, the team sorted through a database of over 1.2 million compounds based on their criteria that would bind to AMPAR GluA2 subunit’s N-terminal domain. After optimization of the remaining 50 compounds, they limited it down to three compounds to be tested in the EAE model. (4) Each of these compounds caused a significant reduction in mean clinical scores as well as in other behavioral markers. When they tested cuprizone on the number of oligodendrocytes, percent myelinated axons and the g-ratio. (4) All were postive markers of healthy myelin and oligodendrocytes. Taken together mediating AMPAR induces reduced glutamate excitotoxicity and appears to be an effective promoter of myelin and oligodendrocyte health.

    Considering both drugs in each lab works as CNS protection compared to DMTs there could be benefits to working on a combined Sephin1 and designer drug approach. (3) In Dr. Fang Lui’s lab he used a cuprizone model without inflammation which Dr. Chen used but included a double transgenic mouse for inflammation. If the Sephin1 can protect and delay on set of disease through prolonging ISR, it can allow targeted designer drugs to reduce glutamate excitotoxicity. This would be more beneficial than BZA because it only reduced the g-ratio, but designer drugs have all the postive effects on all markers plus it reduces overall clinical scores. Sephin1 only delays onset of the disease and does not reduce end stage disease progression. These two treatments combined with traditional DMTs to reduce overall T-cell activation and adaptive auto immune system response can be an extremely powerful treatment strategy. The issues will be getting Sephin1 and designer drugs through the rigorous FDA testing and clinical trials. Even in clinical trials human MS is different than EAE or cuprizone with inflammation, which could cause lack of continuity.

    Overall, there are millions of potential compounds that can be synthesized and using AI to find which one’s act on specfic targets allows for drug designing to be maximally effective. Taking these designed drugs and combining treatments can be extremely effect, especially in CNS protection strategies in MS. The current DMTs heavy use in MS can be reduced by these molecular repair approaches.

References

1. Robertson, D., & Moreo, N. (2016). Disease-Modifying therapies in Multiple Sclerosis: Overview and treatment Considerations. PubMed, 33(6), 28–34. https://pubmed.ncbi.nlm.nih.gov/30766181

2. Chen, Y., Podojil, J. R., Kunjamma, R. B., Jones, J. S., Weiner, M., Lin, W., Miller, S. D., & Popko, B. (2019). Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis. Brain, 142(2), 344–361. https://doi.org/10.1093/brain/awy322

3. News-Medical.net. (2023, December 11). Small molecule drug shows promise as potential new treatment for multiple sclerosis. https://www.news-medical.net/news/20231208/Small-molecule-drug-shows-promise-as-potential-new-treatment-for-multiple-sclerosis.aspx

4. Zhai, D., Yan, S., Samsom, J., Wang, L., Su, P., Jiang, A., Zhang, H., Jia, Z., Wallach, I., Heifets, A., Zanato, C., Tseng, C., Wong, A. H., Greig, I. R., & Liu, F. (2023). Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis. Science Advances, 9(49). https://doi.org/10.1126/sciadv.adj6187