Attenuating the experimental autoimmune encephalomyelitis model improves preclinical evaluation of candidate multiple sclerosis therapeutics

Abstract

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), exhibiting hallmarks of both inflammation and neurodegeneration and with limited treatment options. The intricate nature of MS pathophysiology and its variable progression pose severe challenges for the development of effective therapies. The experimental autoimmune encephalomyelitis (EAE) MS model, in its most common form, is an aggressive disease, which is not representative of the MS course and offers a limited time window for drug evaluation. This study aimed to generate an attenuated EAE variant, which extends the clinical testing window while preserving the high incidence of the standard EAE model. Methods: Components of the EAE induction protocol were titrated to develop a milder disease profile. In a subsequent drug trial using the MS medication fingolimod hydrochloride (FTY, Gilenya), the new variant was validated under prophylactic and therapeutic treatment regimens. Results: The attenuated EAE variant retains the standard hallmarks of neuroinflammation and, crucially, significantly extends the time frame for clinical drug testing. Unlike the standard variant, where FTY efficacy could only be demonstrated by prophylactic treatment, the attenuated variant facilitated differentiation of drug effects by therapeutic treatment initiated early in the acute phase of disease. Conclusion: The new EAE variant is suitable for use in preclinical assessment of candidate therapeutics and the identification of targetable molecular mechanisms underpinning disease development and progression. This study illustrates the importance of optimizing and refining the experimental tool to enhance the translational success of the candidate therapeutics for MS.