Insights and challenges on animal models for progressive multiple sclerosis

Progressive multiple sclerosis (PMS) remains a major clinical challenge due to its complex pathophysiology and limited therapeutic options. While disease-modifying therapies have significantly improved prognosis for relapsing forms of multiple sclerosis (RMS), effective treatments for the progressive, neurodegenerative phase are lacking. Animal models have been instrumental in elucidating the molecular mechanisms underlying multiple sclerosis (MS) pathology and have guided the drug development field for MS, yet their ability to faithfully replicate the development of PMS remains debated. The most frequently used animal models are either immune-mediated, viral, or toxin-induced demyelinating models, but none of these are able to fully mimic the complexity of PMS pathology. This review examines the immunopathological features of animal models of PMS and critically evaluates their strengths and limitations for studying the progressive stages of disease. We highlight the variability that currently exists in the experimental autoimmune encephalomyelitis (EAE) field, as methodologies vary between EAE model paradigms which limit comparability. We conclude that no single model recapitulates PMS, however, refined and combined approaches, with careful attention to strain, age, sex, and induction protocol, can improve translational relevance and support development of therapies targeting PMS.