The small molecule FGFR inhibitor infigratinib exerts anti-inflammatory effects and remyelination in a model of multiple sclerosis.

BACKGROUND AND PURPOSE: Fibroblast growth factors (FGF) and receptors (FGFR) have been shown to modulate inflammation and neurodegeneration in multiple sclerosis (MS). The selective FGFR inhibitor infigratinib has been shown efficient in models of cancers. Herein, we aimed to investigate the effects of infigratinib on prevention and suppression of first clinical episodes in MOG35-55 -induced EAE.

EXPERIMENTAL APPROACH: The oral FGFR inhibitor infigratinib was applied over 10 days either from the time of EAE induction or the onset of symptoms. Effects of infigratinib on proliferation, cytotoxicity, and FGFR signalling proteins were studied in lymphocyte cell lines and microglial cells.

KEY RESULTS: In both experiments infigratinib caused sustained beneficial effects on the clinical course. Administration of infigratinib prevented severe first clinical episodes by 40% and suppressed severe first clinical episodes symptoms by 65%. In spinal cord, infiltration of lymphocytes and macrophages/microglia, and destruction of myelin and axons was reduced by infigratinib. Infigratinib enhanced the maturation of oligodendrocytes and increased remyelination. In addition, infigratinib resulted in an increase of myelin proteins and a decrease in remyelination inhibitors. Further, lipids associated with neurodegeneration such as LPC and ceramide were decreased. Proliferation of T cells and microglial cells were reduced by infigratinib.

CONCLUSION AND IMPLICATIONS: The findings of this proof of concept study demonstrate the therapeutic potential of targeting FGFRs in a disease model of MS. Application of oral infigratinib resulted in anti-inflammatory and remyelinating effects. Thus, infigratinib may have the potential to slow disease progression or even to improve the disabling symptoms of MS.