DOI: 10.1002/ame2.70071
Attenuating the experimental autoimmune encephalomyelitis model improves preclinical evaluation of candidate multiple sclerosis therapeutics
Vernise J.T.Lim1
Melanie J.Murphy2
W.Stephen Penrose3
Coral Warr3
M.Cristina Keightley1
Jacqueline M.Orian3
1.Department of Rural Clinical Sciences and Holsworth Biomedical Research Centre,La Trobe University,Bendigo,Australia;La Trobe Institute for Molecular Science,La Trobe University,Bundoora,Australia2.Department of Psychology,Counselling and Therapy,School of Psychology and Public Health,La Trobe University,Bundoora,Australia3.La Trobe Institute for Molecular Science,La Trobe University,Bundoora,Australia;Department of Biochemistry and Chemistry,School of Agriculture,Biomedicine and Environment,La Trobe University,Bundoora,Australia
摘要：Background:Multiple sclerosis(MS)is a chronic disease of the central nervous system(CNS),exhibiting hallmarks of both inflammation and neurodegeneration and with lim-ited 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 attenu-ated 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 neuroinflam-mation and,crucially,significantly extends the time frame for clinical drug testing.Unlike the standard variant,where FTY efficacy could only be demonstrated by pro-phylactic 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 can-didate therapeutics and the identification of targetable molecular mechanisms under-pinning 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.
机标关键词：evaluationcephncepmodelhaloenceattenuatingautoimmune
论文发表日期：2025-08-30
在线出版日期：2025-11-05（本平台首次上网日期，不代表文献的发表时间）
页数：13( 1428-1440 )
英文信息