Exploring the Latest Advances in Narcolepsy Research

Zahra Alam—McMaster University Life Sciences 2024

Narcolepsy is a chronic and neurological sleep disorder, where the brain is unable to control the sleep-wake cycle. This results in excessive daytime drowsiness, sudden and recurring attacks of sleep, hallucinations, sleep paralysis, and disturbed sleep [1]. Narcolepsy is deemed to be a rare condition, as less than 2% of the worldwide population is affected [2]. However, the percentage is estimated to be higher since many cases are either undiagnosed or misdiagnosed. The unpredictability of narcolepsy consisting of uncontrollable urges to fall asleep spontaneously and chronic fatigue drastically affects an individual’s quality of life [2].  

There are two types of narcolepsy: Type 1 (NT1) and Type 2 (NT2). NT1 presents itself to be the more common form. It is characterized by the presence of a symptom called cataplexy, which is the loss of muscle tone, resulting in involuntary muscle weakness and temporary paralysis in response to strong emotions, such as fear or excitement [3]. This is caused by a lack of a brain chemical called hypocretin (or orexin) present in cerebrospinal fluid which is responsible for activating arousal and regulating sleep-wake patterns [2]. 

SOURCE: SLEEPOLIS

Low hypocretin levels are the defining feature of NT1 in narcoleptics (individuals with narcolepsy), and although the true cause of the loss of hypocretin-producing cells remains unknown, research suggests that it is due to an autoimmune reaction. It is suspected that the immune system mistakenly attacks the small group of neurons in the hypothalamus that are responsible for producing this chemical due to variations in the HLA-DQB1 gene or environmental factors such as influenza A virus [1]. There is not much research pertaining to NT2, however, it is known that NT2 differs from NT1 narcoleptics as they do not have cataplexy and have normal levels of hypocretin [1]. Both types of narcolepsy can also occur along with conditions of the central nervous system and brain injuries, specifically to the hypothalamus [1]. 

Despite copious amounts of research, the exact mechanisms of narcolepsy are unknown. As of now, there is still no cure, however, treatments and therapies are being investigated to treat the symptoms. There has been significant evolution in the treatment of narcolepsy within the last year in which mouse models have been used to mitigate the pathogenetic mechanisms of narcolepsy more accurately than ever before. Researchers were able to follow and track T-cells (immune system cells) to determine how the Pandermix influenza vaccination triggers an autoimmune response against orexinergic neurons (hypocretin-producing cells) [4]. This study provides more evidence of narcolepsy being an immune disorder, which has been the focal point of research in this field for decades [4]. Mouse models have also been the vessel through which treatments have been tested. A new breakthrough drug, Danavorexton, is an example of a drug being heavily researched. This drug reduced cataplexy-like episodes and sleep disturbance in mice [5]. This new drug was then administered intravenously in humans in a phase 1 clinical trial, proving to be well  tolerated and have an association with better sleep latency in both NT1 and NT2 patients [5].  

SOURCE: Winship Cancer Institute

This shows promising potential as a therapeutic agent and shows that more clinical trials need to be investigated. Stem cell transplantation and immunotherapy have demonstrated to be new and successful medical initiatives and treatments. For the first time, both hypothalamic stem cell transplantation and immunotherapy are being tested together to treat sleep disorders, with the goal of replacing  the damaged neurons that are unable to produce hypocretin in NT1 cases [6]. 

Overall, there has been significant growth in the field of narcolepsy research. However, in order to fully understand its implications, pathways, and causes, further research is required. Many promising studies have shown great treatment potential, and thus presents hope for success in the future towards combating narcolepsy.  

References

1. Bassetti CLA, Adamantidis A, Burdakov D, Han F, Gay S, Kallweit U, et al. Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nature Reviews Neurology [Internet]. 2019 Jul 19;15(9):519–39. Available from: https://www.nature.com/articles/s41582-019-0226-9 

2. Rahman T, Farook O, Heyat BB, Siddiqui MM. An overview of narcolepsy. IARJSET. 2016 Mar;3:85-7. 

3. Dauvilliers Y, Siegel JM, Lopez R, Torontali ZA, Peever JH. Cataplexy—clinical aspects, pathophysiology and management strategy. Nature Reviews Neurology. 2014 Jun 3;10(7):386–95. 

4. Bernard-Valnet R, Frieser D, Nguyen XH, Khajavi L, Quériault C, Arthaud S, et al. Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy. Brain [Internet]. 2022 May 13 [cited 2022 Nov 29];145(6):2018–30. Available from: https://academic.oup.com/brain/article-abstract/145/6/2018/6581499

5. Evans R, Kimura H, Alexander R, Davies CH, Faessel H, Hartman DS, et al. Orexin 2 receptor–selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proceedings of the National Academy of Sciences. 2022 Aug 22;119(35). 

6. José Ortega-Albás J, López García R, Martínez Martínez A, Carratalá Monfort S, Antonio Royo Prats J, Albiol Varela L, et al. Narcolepsy Treatment: Present and Future. Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy. 2022 Jan 7