An overview of hypocretin based therapy in narcolepsy

ABSTRACT

Introduction: Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed.

Areas covered: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments.

Expert opinion: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.

KEYWORDS:

• Narcolepsy type1
• narcolepsy type2
• hypocretin
• orexin
• sleepiness
• cataplexy

Article highlights

• Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Therefore, hypocretin replacement will be the most essential treatment for narcolepsy, however, this option is still not clinically available.

• There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy.

• Immunotherapy treatments to prevent hypocretin neuronal death should also be developed, but accumulation of many cases are needed to prove the efficacy of this approach.

• Development of non-peptide hypocretin receptor agonists is the most encouraging treatment since systemic administration of a selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in a murine model of narcolepsy.

• Hypocretin receptor antagonists have already been developed and clinically used for the treatments of insomnia less than 20 years after the discovery of hypocretin peptides, their receptors, and their involvement in narcolepsy, a sleep disorder. Considering this rapid progress, it is conceivable that hypocretin based-therapy would become available soon.

• Hypocretin receptor antagonists can also be applied to other types of hypersomnias, such as symptomatic narcolepsy and excessive daytime sleepiness, as hypocretin deficiency was seen in large portions of these disease conditions.

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