a Stanford University Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences , Stanford University School of Medicine , Palo Alto , CA , USA.
Expert Opin Investig Drugs. 2018 Apr;27(4):389-406. doi: 10.1080/13543784.2018.1459561. Epub 2018 Apr 9.
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.
In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments.
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.
猝倒性睡眠症伴发日间过度嗜睡最常见的原因是下丘脑的下丘脑泌素/食欲素神经元缺失（即 1 型猝倒性睡眠症）。由于下丘脑泌素缺乏被认为是猝倒性睡眠症症状的主要原因，因此下丘脑泌素替代将是治疗猝倒性睡眠症的最基本手段。遗憾的是，这种选择在临床上仍然不可用。有许多潜在的方法可以在大脑中替代下丘脑泌素来治疗猝倒性睡眠症，如鼻内给予下丘脑泌素肽、开发小分子下丘脑泌素受体激动剂、下丘脑泌素神经元移植、将下丘脑泌素干细胞转化为下丘脑神经元，以及下丘脑泌素基因治疗。除了这些选择外，还应开发预防下丘脑泌素神经元死亡的免疫疗法。
在这篇综述中，我们概述了猝倒性睡眠症的病理生理学以及猝倒性睡眠症的现有和新兴治疗方法，特别是聚焦于下丘脑泌素受体为基础的治疗方法。
在下丘脑泌素替代策略中，开发非肽类下丘脑泌素受体激动剂目前最具前景，因为新型合成的、选择性下丘脑泌素受体 2 激动剂（YNT-185）的全身给药已被证明可改善啮齿动物模型中猝倒性睡眠症的症状。如果这种方法在人类中有效，那么下丘脑泌素细胞移植或基因治疗技术在未来可能成为现实。
