title: Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice.
abstract: Gene transfer has proven to be an effective neurobiological tool in a number of neurodegenerative diseases, but it is not known if it can correct a sleep disorder. Narcolepsy is a neurodegenerative sleep disorder linked to the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Here, a replication-defective herpes simplex virus-1 amplicon-based vector was constructed to transfer the gene for mouse prepro-orexin into mice with a genetic deletion of the orexin gene. After in vitro tests confirmed successful gene transfer into cells, the gene vector was delivered to the lateral hypothalamus of orexin knockout (KO) mice where the orexin peptide was robustly expressed in the somata and processes of numerous neurons, and the peptide product was detected in the cerebrospinal fluid. During the 4-day life-span of the vector the incidence of cataplexy declined by 60%, and the levels of rapid eye movement sleep during the second half of the night were similar to levels in wild-type mice, indicating that narcoleptic sleep-wake behavior in orexin KO mice can be improved by targeted gene transfer.
authors.affiliation: West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.forename: Stephen
authors.initials: S
authors.lastname: Thankachan
authors.forename: Satvinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Suraiya
authors.initials: S
authors.lastname: Begum
authors.forename: Carlos
authors.initials: C
authors.lastname: Blanco-Centurion
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.forename: Priyattam J
authors.initials: PJ
authors.lastname: Shiromani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D007026:Hypothalamic Area, Lateral / Q000166:cytology / Q000378:metabolism* / Q000601:surgery; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009290:Narcolepsy / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012890:Sleep / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins