Models & Assays

Experimental autoimmune encephalomyelitis (EAE) is a representative animal model, which manifests, like MS, CNS-related histopathological findings, motor deficits and, inflammatory responses. EAE is one of the most successful disease models in the CNS field, and now in its 90th year ², the neuroimmune mechanisms responsible for the phenotype have been well described ³. The immunomodulator, fingolimod, a sphingosine 1-phosphate (S1P) modulator, is the first oral drug that has been approved for treating MS and has been broadly used as a positive control in the EAE mouse model ^4-7.

We are also pleased to report the pharmacological validation of a NLRP3 inflammasome inhibitor in a mouse model of multiple sclerosis, specifically experimental autoimmune encephalomyelitis (EAE). Our latest results indicate that MCC950 is instrumental in reducing pro-inflammatory cytokines within the central nervous system and in enhancing motor function in the affected animals.

Fingolimod treatment prevents disease progression in EAE

Figure 1: Clinical score – comparison of prophylactic and therapeutic dosing of fingolimod

The prophylactic group was given fingolimod from day 2 and the treatment group was given fingolimod when 50% of immunized animals had developed clinical signs of EAE. All data are presented as mean ± SEM. **p < 0.01. Naïve: n=6, EAE vehicle: n=14, EAE prophylactic: n=10, EAE treatment: n=10

Translational biomarkers: Increased plasma neurofilament light chain (NfL) in EAE is inhibited by fingolimod

Figure 2: NfL quantification in plasma

NfL levels in plasma were quantified using the Mesoscale discovery platform. All data are presented as mean ± SEM. **p < 0.01. Naïve: n=6, EAE vehicle: n=13, EAE prophylactic: n=10, EAE treatment: n=10

The mechanisms of disease manifestation in EAE are well established. Therefore, the model can be broadly used for neuroimmunology programs beyond MS. Clinical score and NfL measurements can be combined with other analyses to provide a more comprehensive profiling of compound efficacy:

• Quantification of cytokine levels in CNS, spleen, and plasma
• Western immunoblotting to evaluate selected signalling pathways (e.g. NLRP3)
• CNS histopathology