Researchers Identify a Potential Therapeutic Target for Multiple Sclerosis

Inhibiting connexin 43 (Cx43) significantly improved symptoms for patients with chronic progressive multiple sclerosis (MS), according to researchers from Kyushu University in Japan. Their findings, published in Scientific Reports, suggest that use of INI-0602, an investigational oncolytic virus therapy, not only suppressed overproduction of Cx43 but also mitigated demyelination and excessive immune cell infiltration to the nervous system.

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According to the World Health Organization, approximately 1.8 million individuals live with MS around the world. MS is a neurodegenerative, inflammatory demyelinating disease of the central nervous system (CNS) that results in the permanent damage or deterioration the myelin sheathes around nerve fibers, affecting cognitive, emotional, motor, sensory, and visual functions. This can include weakness or numbness in the limbs, vision loss, mood disturbances, lack of coordination, or an inability to walk. MS is difficult to diagnose in its early stages and, like other neurodegenerative disorders, has limited treatment options.^1,2

In 2013, the researchers from Kyushu found an increase in Cx43 in astroglia cells around chronic MS lesions, suggesting that it may play a more pivotal role in promoting neuroinflammation. Cx43 is a protein that forms gap junctions, crucial channels for cell-to-cell communication, and plays a key role in regulating the immune system. When overexpressed, this can lead to enhanced cell signaling that contributes to neuroinflammation and demyelination.^3,4

In collaboration with the International University of Health and Welfare, the researchers furthered their investigation of Cx43 as a potential therapeutic target for MS in an experimental mouse model. In the study, the mice received either 40 mg/kg of INI-0602 or saline every other day from days post-immunization 17 to 50.⁴

The findings showed that mice treated with INI-0602 exhibited significant clinical improvement in the chronic phase of experimental autoimmune encephalitis (EAE), the animal model of MS. Additionally, INI-0602 reduced demyelination and levels of CD3+ T cells, macrophages, and reactive astrocytes, suggesting that it may help modulate Immune cell infiltration in the CNS.⁴

Through cerebrospinal fluid analysis, the researchers observed that INI-0602 treatment had a significantly reduced on pro-inflammatory cytokines. It decreased levels of IL-6, an inflammatory marker, and increased levels of IL-10, an anti-inflammatory marker, at an early stage (dpi 24). At a later stage (dpi 50), the drug also reduced levels of IFN-γ and MCP-1. INI-0602 also altered calcium signaling in astroglia, reducing their ability to promote inflammation.⁴

Overall, the study results show promise for the advancement of therapeutic strategies for treating chronic progressive MS. By inhibiting Cx43 with INI-0602, researchers have demonstrated a significant improvement in clinical symptoms and a reduction in key markers of disease activity. Continued research and clinical trials will be crucial in determining the broader applicability and safety of INI-0602 for patients with MS.

“We plan to conduct clinical trials in the future to evaluate the safety and efficacy of INI-0602 in human patients with MS,” said Ryo Yamasaki, MD, PhD, associate professor from the Faculty of Medical Sciences at Kyushu University, in a news release. “Additionally, we also plan to look at the molecular mechanisms of Cx43 in influencing neuroinflammation and demyelination in detail.”³

References

1. Multiple sclerosis. Mayo Clinic. December 24, 2022, Accessed August 1, 2024. https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269

2. Multiple sclerosis. World Health Organization. August 7, 2023. Accessed August 1, 2024. https://www.who.int/news-room/fact-sheets/detail/multiple-sclerosis

3. A new therapeutic target offers a promising pathway for multiple sclerosis treatment. News Release. July 25, 2024. Accessed August 1, 2024. https://www.eurekalert.org/news-releases/1052677

4. Takase E.O., Yamasaki R, Nagata S, et al. Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model. Sci Rep. May 13, 2024. doi:10.1038/s41598-024-61508-2