Narcolepsy is now considered a neurodegenerative disorder and as with other diseases where CNS neurons die it is necessary to explore new strategies to transfer genes to restore function. Here we propose developing a gene transfer approach that will serve as a neurobiological tool to understand the networking underlying narcolepsy and also to ultimately reverse symptoms. We have created a replication-defective HSV-1 amplicon vector to transfer the gene for mouse preprohypocretin together with reporter genes into hypocretin null mice. Our very strong preliminary data shows abundant and robust expression of hypocretin in the lateral hypothalamus of hypocretin null mice along with unambiguous decline of narcoleptic symptoms. We are proposing an integrated series of in vitro and in vivo aims that will serve as a foundation for a more comprehensive effort to utilize the gene transfer approach to reverse the symptoms of narcolepsy in hypocretin null mice. Appropriate experiments with controls are proposed to strengthen the conclusions. Here, we are focusing on transferring the gene for mouse preprohypocretin because this neuropeptide can be easily identified using simple immunohistochemical procedures. We will then migrate to transferring the gene for the receptor, a much more difficult task since there is no good antibody that will allow for verification of the gene transfer. Our overall strategic intent is to transfer the gene for the hypocretin 2 receptor in canine narcolepsy, thereby replacing a mutated receptor gene with a healthy one.

Public Health Relevance

Narcolepsy is now considered a neurodegenerative disorder and it is necessary to explore new strategies to treat the disease. The significance of this project is that it will develop a gene transfer approach that will serve as a neurobiological tool to understand the networking underlying narcolepsy and also to ultimately restore some function. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL091363-01A1
Application #
7470399
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Twery, Michael
Project Start
2008-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$173,836
Indirect Cost
Name
Harvard University
Department
Neurology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Meng; Blanco-Centurion, Carlos; Konadhode, Roda Rani et al. (2016) Orexin gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice. Eur J Neurosci 43:681-8
Blanco-Centurion, Carlos; Liu, Meng; Konadhode, RodaRani et al. (2013) Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep 36:31-40
Liu, Meng; Blanco-Centurion, Carlos; Konadhode, RodaRani et al. (2011) Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci 31:6028-40
Liu, Meng; Thankachan, Stephen; Kaur, Satvinder et al. (2008) Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci 28:1382-93