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Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice

Authors

  • Meng Liu,

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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  • Stephen Thankachan,

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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    • *

      S.T. and S.K. contributed equally to the project.

  • Satvinder Kaur,

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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    • *

      S.T. and S.K. contributed equally to the project.

  • Suraiya Begum,

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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  • Carlos Blanco-Centurion,

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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  • Takeshi Sakurai,

    1. Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
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  • Masashi Yanagisawa,

    1. Howard Hughes Medical Institute and University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Rachael Neve,

    1. Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA
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  • Priyattam J. Shiromani

    1. West Roxbury Veterans Administration Medical Center and Harvard Medical School, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA
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Dr P. J. Shiromani, as above.
E-mail: pshiromani@hms.harvard.edu

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.

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