Animal Models of Narcolepsy: From Orexin Deficiency to Immune Mechanisms and Regenerative Therapies

Animal models have been pivotal in uncovering the orexin (hypocretin) system as the fulcrum of sleep–wake regulation and in shaping therapeutic discovery for narcolepsy. Early canine and murine models established that orexin loss underlies narcolepsy type 1, while conditional and receptor-specific manipulations refined mechanistic insight. However, current paradigms capture only fragments of the human phenotype, often exaggerating cataplexy and under-representing narcolepsy type 2. Here, we follow the evolution of narcolepsy modelling from classical knockout and receptor-deficient systems to immune-driven and cell-replacement models, identifying critical translational gaps and proposing strategies to bridge them. We highlight how immune-competent mouse lines, astrocyte-to-neuron reprogramming, and patient-derived hypothalamic organoids bridge pathogenic insight with therapeutic innovation. Integrating these advances with small-molecule OX2R agonists, gene therapy, and multi-omics-based patient stratification defines a roadmap for moving beyond symptomatic control. This review seeks to unify immune, cellular, and computational perspectives to guide the next generation of animal models toward the prevention, repair, and long-term cure of narcolepsy.