Prayitno, CC BY 2.0, via Wikimedia Commons
Doctors Emmanuel Mignot and Masashi Yanagisawa have been awarded the 2023 Breakthrough Prize in Life Sciences in September this year. This award honoured their successes in elucidating the aetiology of narcolepsy. Nicknamed “The Oscars of Science”, the Breakthrough Prize is the most lucrative in the field; the two research teams, spanning across two continents, will share $3 million for their ground-breaking discoveries.
Narcolepsy is a rare neurological disorder affecting 1% of the population. Characterised by spontaneous attacks of daytime sleepiness, it has a major impact on quality of life and is diagnosed after decline in performance at school, or a motor vehicle accident. 70% of cases of narcolepsy are accompanied by cataplexy: rapid and transient muscle paralysis that can cause collapse despite being fully awake, often being precipitated by strong emotion such as laughter.
Patients have described being fully conscious, but physically incapable of stopping, despite painful attempts made by paramedics to wake them during an attack of cataplexy in public. Narcolepsy can also present with disturbing sleep paralysis and hypnagogic and hypnopompic hallucinations. Previous scarce knowledge of narcolepsy resulted in poorly managed symptoms and a lack of available drugs.
Attempts to mitigate symptoms currently include napping, strict diet, and, in some cases, prescription of stimulants such as Modanifil (despite contentious efficacy and extensive side effects).
In 1986, Mignot was commissioned in Stanford University to research a French drug for narcolepsy as part of his military service. He set out to identify the genetic mutation underlying the disorder by inbreeding narcoleptic dogs in the lab. This goal was ambitious, as not only did it precede the Human Genome Project, but Mignot was a psychiatrist not a geneticist. “Everyone told me that was totally crazy. They said I would never succeed”, he explained. Despite taking 10 years to accomplish, Mignot successfully identified that the mutated gene belonged to a cell membrane receptor for a mystery molecule.
Simultaneously, Yanagisawa’s team in the University of Tsukuba, Japan, were performing protein refining studies. These revealed the mystery molecule as orexin—a sleep hormone that acts in the basal forebrain and cortex to sustain wakefulness during the daytime.
Yanagisawa then performed forward genetic studies in mice with sleep-wake abnormalities, discovering that mice which lacked the orexin gene were no longer nocturnal and instead suffered sleep attacks at night. However, when injected with orexin, they remained awake.
The separate but simultaneous research led to a thrilling convergence of information that resulted in the 1999 discovery that orexin acted on receptors to induce wakefulness and block REM sleep, and narcolepsy was subsequently caused by orexin deficiency in patients. Further genetic research by Mignot revealed a strong association between HLA genes, T cell antigen receptor genes, and narcolepsy. This lead him to theorise that narcolepsy was an autoimmune disorder that selectively destroyed orexin-producing neurons in the brain.
The field of neurological autoimmunity is “beginning to explode”, as Mignot described at the 2022 World Sleep Conference in Rome. Furthermore, this finding could lead to robust diagnosis of narcolepsy by a blood test for autoantibodies to identify half the sufferers believed to have gone undiagnosed so far.
Following the Orexin discovery, clinical trials of the orexin analogue Tak-925 have shown outstanding preliminary results, with subjects able to sustain wakefulness for the full duration of the Maintenance of Wakefulness Test—a finding that has never been observed before with other drugs.
Takeda of Japan are hopeful that a drug for narcolepsy could be on the market in the next few years. Such wakefulness drugs could be multifunctional and potentially also utilised in the management of fatigue for patients suffering from severe depression.
The thorough and innovative work of Yanagisawa and Mignot has provided a major impetus in the field of sleep research, leading to new vistas and hope for individuals suffering with sleep disorders. Sleep is a complex and fascinating process. The more we uncover about sleep, the more extensive and relevant the picture becomes.
