Research Report: Effect of Bruton Tyrosine Kinase Inhibitor Evobrutinib on Myelin Repair and CNS Inflammation in Multiple Sclerosis

Background Introduction

Multiple Sclerosis (MS) is a demyelinating disease of the Central Nervous System (CNS) where the myelin sheath of patients is damaged by inflammation. Traditionally, MS is considered to be primarily triggered by infiltrating immune cells, and clinical intervention strategies mainly focus on managing the activation, infiltration, and effector functions of peripheral immune cells. However, these therapies can reduce the frequency of acute MS relapses to a certain extent but are ineffective in controlling non-relapsing progression, known as chronic progression.

Chronic progression is not limited to a specific disease stage and is not exclusive to primary or secondary-progressive MS. This type of progression begins early and is mainly driven by mechanisms within the CNS. Current strategies to address this type are still very scarce. Studies have indicated that the driving factors of chronic progression are mainly the innate immune cells within the CNS—microglia. Among them, Bruton’s tyrosine kinase (BTK) is a key enzyme in the activation of B cells and mononuclear/phagocytic cells (such as macrophages and microglia). Inhibiting BTK may be an effective strategy to control chronic progression.

Research Source

This study was completed by Anastasia Geladaris, Sebastian Torke, and others from institutions including Georg August University, Charité - Universitätsmedizin Berlin, and EMD Serono Inc. The study was published in 2024 in the journal “Acta Neuropathologica.”

Research Process and Methods

Experimental Design:

• Subjects and Samples: The study primarily used mouse models to simulate MS, including chronic experimental autoimmune encephalomyelitis (EAE) and toxic demyelination models.
• Medication: The BTK inhibitor Evobrutinib was used to evaluate its effects on inhibiting microglial inflammatory activation and promoting myelin repair.

Main Steps:

1. BTK Expression Detection:

   • The study first detected BTK expression in mouse and human MS tissues using in vitro and in vivo experiments. BTK was found to be highly expressed in microglia and upregulated in chronic EAE and MS tissues.
   • Immune cells from the CNS and peripheral lymphoid organs (such as the spleen) were isolated, and protein and mRNA expression levels were detected. It was found that BTK expression was significantly upregulated in microglia and lymphocytes in immunized MS model mice.

2. Effect of Evobrutinib Treatment on EAE:

   • In the actively induced EAE model, Evobrutinib treatment significantly reduced clinical symptoms, and markers of microglial inflammatory reactivity were significantly lowered.
   • In the chronic EAE model, Evobrutinib not only effectively inhibited microglial activation but also reduced the expression of antigen-presentation-related markers in macrophages infiltrating the brain.
   • In the passive EAE model, through pre-treatment and transfer of already activated T cells, it was observed that inflammation levels were reduced and clinical performance improved after Evobrutinib treatment, indicating that Evobrutinib has immunomodulatory effects within the CNS.

3. Effect of Evobrutinib on Myelin Repair:

   • In the toxicity-induced demyelination model without inflammatory drivers, Evobrutinib treatment promoted the clearance of myelin fragments by microglia and significantly increased the speed of myelin remodeling and nerve function recovery.

Data Analysis:

Various statistical methods were used in the study, including two-tailed t-tests and one-way ANOVA, to compare sample data under different treatment conditions, showing significant effects.

Main Results

1. BTK Expression in MS: BTK is highly expressed in microglia and significantly upregulated in chronic EAE and MS tissues, especially in human chronic active MS lesions.
2. Therapeutic Effect of Evobrutinib: In active and chronic EAE models, Evobrutinib can significantly reduce clinical symptoms and the activation state of inflammatory cells; in the passive EAE model, pre-treatment with Evobrutinib significantly reduced microglial inflammatory reactivity, indicating the potential central nervous system targeting action of the drug.
3. Promoting Myelin Repair: In the non-inflammatory toxicity-induced demyelination model, Evobrutinib significantly enhanced myelin remodeling and functional recovery by promoting the clearance of myelin fragments by microglia.

Research Conclusion

1. Scientific Value: The research demonstrated the important role of BTK in microglial activation and MS progression. Inhibiting BTK can control chronic progression and promote myelin repair.
2. Application Value: Evobrutinib, as a BTK inhibitor, can not only alleviate the activation of peripheral immune cells but also directly regulate microglia within the CNS, showing potential for treating chronic progression in MS.
3. Uniqueness: This study first provided direct evidence of BTK activation in MS and its inhibition effects on microglia and myelin repair, providing solid foundational data for future clinical applications.

Research Highlights

1. Inhibiting Microglial Activation: The study detailed the dual regulatory effect of Evobrutinib on microglia, showing reduced inflammatory reactivity and enhanced fragment clearance ability.
2. Promoting Myelin Repair: In the toxic demyelination model, Evobrutinib promoted myelin remodeling and neurological recovery, opening new avenues for future treatments.
3. Drug Penetration into CNS: Evobrutinib can cross the blood-brain barrier, exerting effective concentration and action within the brain, suggesting the possibility of new MS treatments.

This study lays the scientific foundation for the use of BTK inhibitors in the treatment of multiple sclerosis and shows their potential in controlling disease progression and promoting neural repair.