Rescue of Narcoleptic Orexin Neuron-Ablated Mice by Ectopic Overexpression of Orexin Peptides

Human narcolepsy-cataplexy is a debilitating neurological disease characterized by excessive daytime sleepiness, premature transitions to REM sleep (called sleep-onset REM periods), and cataplexy (sudden bilateral skeletal muscle weakness without impairment of consciousness). Narcolepsy-cataplexy affects males and females equally, with an estimated prevalence of 0.02–0.18% within white populations. Most cases of narcolepsy-cataplexy are idiopathic, and symptoms appear around adolescence and last throughout life. Several studies have reported a strong association between certain class II HLA haplotypes on human chromosome 6 and narcolepsy-cataplexy; HLA DQB1*0602 and DQA1*0102 are found in up to 90% of affected populations, compared with 12–38% in the general population, suggesting that autoimmunity plays a role in the disorder. Excessive sleepiness is treated using psychostimulants, such as amphetamines, and modafinil; cataplexy is treated with tricyclic antidepressants such as clomipramine. However, this therapeutic regimen is problematic owing to limited effectiveness, undesirable side effects such as insomnia or symptom rebounds, and the potential for abuse (1,2).