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

Animal models have been pivotal in uncovering the hypocretin (orexin) system as the fulcrum of sleep–wake regulation and in shaping therapeutic discovery for narcolepsy. Early canine and murine models established that hypocretin 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. Recent advances, including immune-mediated models, astrocyte-to-neuron reprogramming, and patient-derived hypothalamic organoids, are beginning to align pathogenesis with translational innovation. Parallel developments in small-molecule OX2R agonists, gene therapy, and regenerative cell-based strategies hold promise for disease modification, while digital phenotyping and multi-omics integration promise refined patient stratification. This review synthesizes past progress and future directions, outlining a roadmap from descriptive modelling to precision medicine. By bridging immune, cellular, and computational approaches, narcolepsy research is poised to move beyond symptomatic control toward prevention, repair, and long-term cure.