To characterize a central nervous system (CNS)-penetrant, tolebrutinib-like Bruton’s tyrosine kinase inhibitor (BTKi) in murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) for its potential to modulate disease progression and expression of genes linked to disease-associated microglia (DAM).

Female C57BL/6 mice were immunized with MOG_35-55 peptide (250 µg/mouse; two subcutaneous injections in the lower back) to induce EAE. Animals were randomized to receive vehicle (n=15) or oral BTKi (15 mg/kg; n=15), starting at clinical score of 1.0–1.5. Treatment groups were blinded until after final data analysis. Cohorts were monitored daily for development and severity of disease symptoms. After 10 days of treatment, spinal cord and plasma samples were taken for transcriptome analysis and neurofilament heavy chain (NfH) concentration measurement, respectively.

We extended our previous in vivo findings from a demyelination model by demonstrating that dosing with a BTKi halted disease progression in an immune-mediated model of MS. This therapeutic benefit was accompanied by modulated expression of genes associated with activated microglia, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS.