Establishing a human microglia model to evaluate novel therapies for multiple sclerosis progression
by Alica Blenkle
Date of Examination:2025-07-31
Date of issue:2025-09-22
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Dr. Maria-Patapia Zafeiriou
Persistent Address:
http://dx.doi.org/10.53846/goediss-11523
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Abstract
English
Despite significant advances in the development of therapies for multiple sclerosis (MS), treating disease progression remains a major clinical challenge. MS progression refers to the accumulation of neurological disability independent of relapse activity and is driven by chronic neurodegeneration. Microglia-mediated inflammation has been implicated in the mechanisms leading to disease progression and neurodegeneration, making the regulation of microglial states a promising therapeutic strategy to slow the progression of MS. To elucidate the mechanisms underlying microglia-driven inflammation in MS and to support the development of disease modifying therapies for relapses, the use of in vivo animal models and animal-derived in vitro systems have been essential. However, the translational success of therapies targeting MS progression has been limited due to the absence of human-specific disease mechanisms and the inability of current models to fully recapitulate the pathological features of MS progression. Consequently, there is an increasing need for human-derived in vitro microglia models to more accurately investigate the therapeutic potential of drugs for the treatment of MS progression. In this study, human induced pluripotent stem cells (hiPSCs) were used to generate hiPSC-derived microglia (iMG). Comprehensive phenotypic and functional characterization demonstrated that iMG reflect key microglial features relevant to MS progression, supporting their use as a physiologically relevant model to test therapeutics targeting microglia and finally disease progression. One promising therapeutic strategy involves the inhibition of Bruton’s tyrosine kinase (BTK), a key modulator of Fc receptor (FcR)-induced pro-inflammatory microglial responses. Four BTK inhibitors, evobrutinib, remibrutinib, tolebrutinib, and fenebrutinib, have been evaluated for their effects on microglia, with tolebrutinib recently showing promising clinical results in reducing the risk of MS progression. However, differences in experimental design, models used, and dosages across these studies have complicated direct comparisons. To address this, the second part of this study systematically evaluated the efficacy of the BTK inhibitors in modulating microglial responses following FcR-dependent stimulation, using a standardized, side-by-side comparison in human-derived iMG. All investigated compounds influenced microglia activity, reducing the expression of molecules involved in antigen presentation and/or FcR-induced chemokine secretion. Notably, while evobrutinib and fenebrutinib required high concentrations to exert effects, remibrutinib and tolebrutinib were effective at lower doses. These findings highlight the potential of BTK inhibitors, particularly remibrutinib and tolebrutinib, to regulate microglial functions involved in pathogenic T cell activation and migration, offering a promising therapeutic strategy for MS progression.
Keywords: Microglia; Induced Pluripotent Stem Cells; Multiple sclerosis; Bruton’s tyrosine kinase (BTK); Evobrutinib; Remibrutinib; Tolebrutinib; Fenebrutinib; MS progression
