Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination

Bruton's tyrosine kinase (Btk) is an emerging target in Multiple Sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, Btk regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of Btk inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with Experimental Autoimmune Encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a Btk inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic Btk inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant Btk inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, Btk inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.