Orexin Restoration in Narcolepsy: Breakthroughs in Cellular Therapy

Narcolepsy is a chronic neurodegenerative disorder defined by the selective loss of orexin-producing neurons in the lateral hypothalamus, leading to excessive daytime sleepiness and cataplexy. While pharmacological therapies have evolved to mitigate symptoms, they fail to address the core pathology-orexin deficiency. This narrative review examines the potential of orexin cell transplantation as an innovative therapeutic approach to restore orexin signalling and treat the root cause of narcolepsy. We begin by examining the clinical features, pathophysiology, and diagnostic criteria of narcolepsy, focusing on the essential role of orexins in regulating the sleep-wake cycle and the neurobiological mechanisms underlying cataplexy. The review then explores experimental therapeutic approaches, including hypothalamic tissue grafts, gene therapy, and immortalised orexin-expressing cell lines, highlighting their potential to address the orexin deficit in narcolepsy. While preclinical studies show that transplanted orexin cells can integrate into host neural networks, enhance sleep stability, and decrease the frequency of cataplexy in animal models, several challenges remain. Immortalised orexin cell lines offer a scalable and consistent option for transplantation therapies. However, immune rejection, long-term cell survival, and complete functional integration persist. These translational hurdles must be addressed to bring these therapies to clinical practice. This review underscores the need for continued research to overcome these barriers and optimise cell-based therapies for narcolepsy.