The small molecule fibroblast growth factor receptor inhibitor infigratinib exerts anti-inflammatory effects and remyelination in a model of multiple sclerosis.

BACKGROUND AND PURPOSE: Fibroblast growth factors and receptors (FGFR) have been shown to modulate inflammation and neurodegeneration in multiple sclerosis (MS). The selective FGFR inhibitor infigratinib has been shown to be effective in cancer models. Here, we investigate the effects of infigratinib on prevention and suppression of first clinical episodes of myelin oligodendrocyte glycoprotein (MOG)35-55 -induced experimental autoimmune encephalomyelitis (EAE) in mice. EXPERIMENTAL APPROACH: The FGFR inhibitor infigratinib was given over 10 days from the time of experimental autoimmune encephalomyelitis induction or the onset of symptoms. The effects of infigratinib on proliferation, cytotoxicity and FGFR signalling proteins were studied in lymphocyte cell lines and microglial cells. KEY RESULTS: Administration of infigratinib prevented by 40% and inhibited by 65% first clinical episodes of the induced experimental autoimmune encephalomyelitis. In the spinal cord, infiltration of lymphocytes and macrophages/microglia, destruction of myelin and axons were 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 lysophosphatidylcholine and ceramide were decreased as were proliferation of T cells and microglial cells. CONCLUSION AND IMPLICATIONS: This proof of concept study demonstrates the therapeutic potential of targeting FGFRs in a disease model of multiple sclerosis. 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 multiple sclerosis.

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis.

Recombinant beta interferons-1 (IFNß-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNß-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNß-1a versus the combined application of s.c. IFNß-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1ind-/- mice) in MOG35-55-induced EAE. IFNß-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and Fgfr1ind-/- mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNß-1a (400 ng/mL). Application of IFNß-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNß-1a in Fgfr1ind-/- mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1ind-/- mice treated with IFNß-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNß-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.