Drug Discovery Opinion

Although the disorder is not very well known, narcolepsy is thought to affect 1 in 2000 individuals and this figure may be higher as a consequence of under-reporting and under-diagnosis. The most common symptom is excessive daytime sleepiness (EDS), which may be accompanied by sudden loss of muscular control (cataplexy) triggered by strong emotions. Narcoleptics may also experience sleep paralysis (short periods of paralysis when waking or falling asleep), hypnagogic or hypnopompic hallucinations (vivid images or sounds, respectively, when waking or falling asleep) or automatic behaviour (when routine activities are continued during a sleep episode).

For the last ten years it has been known that narcoleptics have a deficiency in hypocretin (orexin), a neurotransmitter involved in control of sleep/wakefulness. In parallel with the neurotransmitter deficiency there is a massive loss of hypothalamic neurons that produce hypocretin and it has been hypothesised that this results from an autoimmune response.

Swiss scientists have now identified autoantibodies to Tribbles homolog 2 (Trib2), an autoantigen previously identified in autoimmune uveitis, in narcolepsy patients. The team developed a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Having identified enrichment of Trib2 in the mouse hypocretin neurons, the team went on to analyse sera from narcoleptics. Narcolepsy patients with cataplexy had higher Trib2-specific antibody titres compared with either normal controls or patients with other inflammatory neurological disorders. Trib2-specific antibody titres were highest early after narcolepsy onset, sharply decreased within 2–3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. Additionally, high Trib2-specific antibody titres correlated with the severity of cataplexy.

The study, published in the Journal of Clinical Investigation, provides the first evidence that narcolepsy is an autoimmune disorder.

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