Development of a novel gene therapy on narcolepsy using AAV vectors and artificial GPCRs

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The loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. However, the precise neural mechanisms downstream of orexin neurons remain unknown.We found that the locus coeruleus noradrenergic and dorsal raphe serotonergic neurons play differential roles in the regulation of sleep/wakefulness by orexin neurons: the former stabilizes wakefulness episodes (reduce sleepiness) and the latter suppresses cataplexy in mice. In addition, we developed a system to suppress narcolepsy in mice by artificially activating these neurons using recombinant AAV vectors and an artificial GPCR called DREADD.