Abstract Details

Title The Multi-kinase Inhibitor AZD4547 Reduces Inflammation and Neurodegeneration, and Enhances Remyelination in a Mouse Model of Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 6-008

Objective To characterise the effects of multi-kinase inhibition of FGFR, VEGFR2 and CSF1R on the disease course, inflammation and degeneration in EAE.

Background FGF signalling pathways play a key role in the pathology of multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE). Selective inhibition of FGFR by the brain-penetrant compound infigratinib prevented first clinical episodes by 40%, reduced demyelination, increased the number of oligodendrocytes in lesions and enhanced remyelination. Previous studies have shown that knockout or pharmacological inhibition of other receptors such as VEGFR2 and CSF1R have beneficial effects in EAE.

Design/Methods EAE was induced using the MOG_35-55peptide in eight-week-old female C57BL/6J mice. Mice were treated with the multi-kinase inhibitor AZD4547 (6.25 mg/kg or 12.5 mg/kg vs. placebo) over 10 days either from the time of EAE induction (prevention experiment) or the onset of symptoms (suppression experiment). Effects on inflammation, degeneration/regeneration and on FGF pathways were assessed.

Results Treatment with AZD4547 reduced the severity of the first clinical episodes by 84.6% (prevention experiment) or 81% (suppression experiment). Mice treated with 12.5 mg/kg of AZD4547 hardly showed any symptoms in the chronic phase of EAE. In both experiments, reduced infiltration of lymphocytes, and macrophages/microglia, less demyelination, and preserved axonal density in lesion areas were observed. Further, treatment with AZD4547 led to a higher number of oligodendrocyte precursor cells and mature oligodendrocytes in lesion areas. Additionally, AZD4547 modulated the expression of FGFR2, CSF1R and VEGFR2. No reduction of body weight was detected.

Conclusions Multi-kinase inhibition of FGFR1-3, CSF1R and VEGFR2 resulted in beneficial effects on the disease course, inflammation, oligodendrocyte numbers, and neurodegeneration. Better clinical outcome by AZD4547 compared with selective inhibition of FGFR1-3 may be due to multi-kinase inhibition. Since current MS therapeutics fail to halt disease progression, targeting of several receptors associated with inflammation and neurodegeneration may be a promising therapeutic approach.

Authors/Disclosures
Kian Shirvanchi PRESENTER	Mr. Shirvanchi has received research support from University of Giessen.
Fynn Gurski	No disclosure on file
Vinothkumar Rajendran (Justus-Liebig University)	Mr. Rajendran has nothing to disclose.
Ranjithkumar Rajendran (Justus Liebig University)	Mr. Rajendran has nothing to disclose.
Fevronia- Foivi Megalofonou	No disclosure on file
Christine Stadelmann-Nessler	No disclosure on file
Srikanth Karnati	No disclosure on file
Martin Berghoff, MD, FAAN (BundeswehrZentralkrankenhaus Koblenz)	Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MerckSerono. Dr. Berghoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb.

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