title: Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice.
abstract: OBJECTIVE
  Narcolepsy is caused by selective loss of the orexin/hypocretin-producing neurons of the hypothalamus. For patients with narcolepsy, chronic sleepiness is often the most disabling symptom, but current therapies rarely normalize alertness and do not address the underlying orexin deficiency. We hypothesized that the sleepiness of narcolepsy would substantially improve if orexin signaling were restored in specific brain regions at appropriate times of day.
  
  
  METHODS
  We used gene therapy to restore orexin signaling in a mouse model of narcolepsy. In these Atx mice, expression of a toxic protein (ataxin-3) selectively kills the orexin neurons.
  
  
  METHODS
  To induce ectopic expression of the orexin neuropeptides, we microinjected an adeno-associated viral vector coding for prepro-orexin plus a red fluorescence protein (AAV-orexin) into the mediobasal hypothalamus of Atx and wild-type mice. Control mice received an AAV coding only for red fluorescence protein. Two weeks later, we recorded sleep/wake behavior, locomotor activity, and body temperature and examined the patterns of orexin expression.
  
  
  RESULTS
  Atx mice rescued with AAV-orexin produced long bouts of wakefulness and had a normal diurnal pattern of arousal, with the longest bouts of wake and the highest amounts of locomotor activity in the first hours of the night. In addition, AAV-orexin improved the timing of rapid eye movement sleep and the consolidation of nonrapid eye movement sleep in Atx mice.
  
  
  CONCLUSIONS
  These substantial improvements in sleepiness and other symptoms of narcolepsy demonstrate the effectiveness of orexin gene therapy in a mouse model of narcolepsy. Additional work is needed to optimize this approach, but in time, AAV-orexin could become a useful therapeutic option for patients with narcolepsy.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Sandor
authors.initials: S
authors.lastname: Kantor
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Lops
authors.forename: Brian
authors.initials: B
authors.lastname: Ko
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Clain
authors.forename: Erika
authors.initials: E
authors.lastname: Clark
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000502:physiology; D009290:Narcolepsy / Q000235:genetics / Q000628:therapy*; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D000068797:Orexins; D017286:Polysomnography; D012890:Sleep / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014851:Wakefulness / Q000235:genetics* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse
keywords: AAV-orexin; ataxin-3; cataplexy; gene therapy; hypothalamus; locomotor activity; narcolepsy; wake maintenance
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