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.