Evaluating the Effect of a Bruton’s Tyrosine Kinase Inhibitor in a Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis (P2-3.012)

Objective:

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).

Background:

BTK inhibition may slow disease progression in people with MS by targeting microglia-driven neuroinflammation in the CNS. We previously showed that a structural analogue of the BTKi tolebrutinib can reduce BTK-dependent inflammatory signalling in microglia in the mouse brain, using the cuprizone-mediated model of demyelination.

Design/Methods:

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.

Results:

BTK inhibition significantly reduced the clinical score in the EAE mice, with significant differences between treatment groups starting after two days of treatment and continuing until end of study (Day 10). BTK inhibition significantly reduced plasma Nfh concentrations. A BTK-dependent transcriptional signature was identified, with BTK inhibition found to modulate pathways relevant to MS pathology. BTK inhibition modulated mRNA expression of genes that had previously been linked to DAM and/or are associated with BTK-signalling.

Conclusions:

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. Disclosure: Dr. Gruber has received personal compensation for serving as an employee of Sanofi. Dr. Gruber has received stock or an ownership interest from Sanofi. Dr. Blazier has received personal compensation for serving as an employee of Sanofi. Lan Lee has nothing to disclose. Dr. Ryan has nothing to disclose. Dr. Cheong has received personal compensation for serving as an employee of Sanofi. Ms. Havari has received personal compensation for serving as an employee of sanofi. Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has received stock or an ownership interest from Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care. Dimitry Ofengeim has received personal compensation for serving as an employee of Sanofi. Dimitry Ofengeim has received stock or an ownership interest from Sanofi. Dimitry Ofengeim has received personal compensation in the range of $500-$4,999 for serving as a Study Section Reveiwer with NIH.