Targeting Innate-mediated Signaling for Treatment of Multiple Sclerosis
KATSOULAS A. 1, FERREIRA M F. 1, BUCH T. 1
1 Institute of Laboratory Animal Sciences (LTK) UZH, Schlieren, Switzerland
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease that affects a significant proportion of the population. Approximately 15% of MS patients suffer from progressive stages of MS, characterized by a gradual and continuous accumulation of irreversible disability, for which there is currently no effective treatment. While the earlier stages of MS are primarily driven by adaptive immunity, the mechanisms underlying the progressive stages involve innate immune dysfunctions. Precise triggers of these disease stages remain unclear, but emerging evidence suggests that Pattern Recognition Receptors (PRRs), which coordinate the innate immune response, may play a significant role. In our studies utilizing a mouse model of MS, Experimental Autoimmune Encephalomyelitis (EAE), we demonstrated that disrupting certain innate signaling pathways had unexpected impact on disease outcome, with certain molecules driving the disease or providing protection against it. Specifically, our research revealed that mice deficient in specific innate molecules exhibited resistance to EAE, as evidenced by significantly lower clinical scores and restored myeloid cell percentages compared to controls. Interestingly, these molecules have also been shown to be upregulated in peripheral blood mononuclear cells (PBMCs) of MS patients and associated with MS brain lesions. Building upon these findings, we identified an efficient compound that targets a mechanism controlled by innate signaling. We have conducted in vitro studies using mouse and human cells, as well as in vivo experiments. Remarkably, the compound demonstrated nearly 90% efficiency in reducing intended target in human monocytes and conferred protection against severe disease development in mice. Currently, our focus is on understanding the cellular and molecular mechanisms behind the critical role of innate signaling in EAE and MS pathogenesis, as well as testing different compounds. Through additional in vivo studies and administration parameters we hope to provide insights into a promising avenue for developing novel therapeutic options for MS.