Emerging therapeutic targets for narcolepsy

Introduction Narcolepsy type 1 (NT1) and type 2 (NT2) are chronic sleep disorders primarily characterized by excessive daytime sleepiness (EDS), disturbed sleep-wake regulation, and reduced quality of life. The precise disease mechanism is unclear, but it is certain that in NT1 the hypocretin/orexin (Hcrt) system is affected. Current treatment options are symptomatic - they improve EDS and/or reduce cataplexy. Complete symptom control is relatively rare - particularly problematic is residual daytime sleepiness. Areas covered This review discusses various emerging treatment targets for narcolepsy. The focus is on the Hcrt receptors but included are also wake-promoting pathways, and sleep-stabilization through GABAergic mechanisms. Additionally, we discuss the potential of targeting the likely autoimmune basis of narcolepsy. PubMed and ClinicalTrials.gov was searched through June 2021 for relevant information. Expert opinion Targeting Hcrt receptors has the potential to alleviate narcolepsy symptoms. Results from ongoing drug development programs are promising, but care needs to be taken when evaluating potential side effects. It is still largely unknown what roles Hcrt receptors play in the periphery and how these might be affected by treatment. Immunotherapies could potentially target the core pathophysiology of narcolepsy, but more work is needed to identify the best therapeutic target for this approach.