Multi-target approaches to prion disease drug discovery: a status update

INTRODUCTION: Prion diseases comprise a heterogeneous group of rare and fatal neurodegenerative disorders characterized by self-propagating misfolding of the cellular prion protein. Although no therapy has yet proven capable of halting disease progression, several promising approaches are beginning to shift the field from repeated disappointment toward cautious but genuine translational optimism. AREAS COVERED: This review examines emerging therapeutic approaches targeting key nodes of prion biology, including prion protein-targeting strategies and interventions directed at cellular pathways involved in disease pathogenesis. The authors further discuss the potential and challenges associated with polypharmacology, such as drug combinations and multi-target-directed ligands, which aim to address the biological complexity of prion disease. EXPERT OPINION: The persistent limitations of single-target therapies for human prion disease emphasize the need to better align therapeutic strategies with disease stage, biological heterogeneity, and network-level pathogenesis. Achieving meaningful therapeutic impact will require an integrated strategy that brings together earlier intervention, improved patient stratification, and rational use of combination and multi-target approaches, supported by advances in biomarkers and experimental modeling.