Treatments targeting Neural Regeneration in Multiple Sclerosis

     Multiple Sclerosis is a chronic autoimmune disease that is distinguished by the destruction of the myelin sheaths within the central nervous system (CNS). With MS your body mistakenly attacks the myelin cells that surround your brain and spinal cord cells. The damaging of the myelin sheath results in nerve signal interruption in bodily functions such as vision, sensation and movement. Specifically, the immune system attacks the oligodendrocytes which are the glial cells responsible for producing myelin. Although the body initiates remyelination to some degree the overall repair process of these cells is left incomplete.

    Oligodendrocyte precursor cells are central to remyelination, and these precursor cells must develop and mature within the inflammatory environment of the central nervous system. Although current therapies focus primarily on immunomodulation and reducing inflammation often through the promotion of apoptosis in immune cells, there has been a growing demand for treatments that actively promote remyelination. There have been two recent developments within this world: the combined use of Sephin1 and bazedoxifene (BZA) to modulate the integrated stress response (ISR) and enhance oligodendrocyte differentiation, and PIPE-307 which is a new drug that promotes remyelination by targeted the muscarinic M1 receptor (M1R) on oligodendrocyte precursor cells. These therapies provide similar mechanisms of action, suggesting an effective strategy for repairing myelin in the inflamed CNS.

      In the study “Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response” by Dr. Yanan Chen et Al. , the researchers demonstrated that the ISR supports proteostasis and protects cells from stress-induced damage. In multiple sclerosis the ISR is activated in oligodendrocytes in response to inflammatory signals such as interferon-gamma (IFN-γ). In their research they discovered Sephin1, a small molecule that increases the ISR, as a possible therapeutic treatment. Sephin1 extends ISR activity, protecting oligodendrocytes and delaying demyelination even in the presence of IFN-γ. Sephin1 was also shown to prolong the phosphorylation of eIF2α, which led to the reduction of global protein synthesis and the promotion of forming RNA stress granules. When coupled with BZA, a drug that promotes the development of oligodendrocyte precursor cells, the combination therapy accelerated early remyelination in a mouse model and led to thicker myelin sheaths than either treatment just by itself. However, the combined therapy did not increase OPC proliferation in the presence of IFN-γ. It was found though that BZA increased OPC differentiation in vitro, suggesting that its major effect lay in encouraging maturation rather than cell growth. This explains the the uses of a coupled therapy: modulating the ISR while also boosting OPC differentiation as a useful method for repairing myelin degradation in MS.

    Alternatively, PIPE-307 has found to target the upstream effects of MS. PIPE-307 is believed to selectively inhibit the M1 receptor, which is significantly expressed in the oligodendrocyte precursor cells. The M1 receptor is also known to suppress the differentiation of the OPCs in inflammatory conditions. In mouse models of experimental autoimmune encephalomyelitis, which is a common animal model of multiple sclerosis, PIPE-307 therapy was found to increase the remyelination and strengthen other functions that were affected by MS. Furthermore, UCSF scientists Jonah Chan, PhD, and Ari Green, MD ,who were the ones who first discovered PIPE-307 therapy, found that in human brain tissue samples PIPE-307 was able to promote remyelination showing its practical potential. PIPE-307 is now also undergoing Phase II clinical trials (VISTA) for relapsing-remitting MS, where its effects on remyelination, visual acuity, cognition and motor function are being evaluated.

    Overall, these findings with the ISR-enhancing combination of Sephin1/BZA and the receptor-specific activity of PIPE-307 represent an important step towards neuroreparative approaches in the treatment of multiple sclerosis. As clinical studies progress integrating these treatments has the possibility to change how multiple sclerosis is treated and supports the transition from immune suppression and towards neural regeneration.

 

References

Chen Y, Quan S, Patil V, et al. Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response. 2023;71(9):2180-2195. doi:https://doi.org/10.1002/glia.24386

News N. New Multiple Sclerosis Drug Regenerates Myelin, Improves Movement - Neuroscience News. Neuroscience News. Published August 5, 2024. https://neurosciencenews.com/myelin-movement-ms-neuropharmacology-37518/

Wexler M. PIPE-307 shows potential to repair myelin in MS mouse model. Multiple Sclerosis News Today. Published August 8, 2024. https://multiplesclerosisnewstoday.com/news-posts/2024/08/08/pipe-307-shows-potential-repair-myelin-ms-mouse-model/