Narcolepsy afflicts 0.025-0.05% of the population and is characterized by excessive daytime sleepiness, cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and increased propensity for rapid-eye-movement (REM) sleep. Although narcolepsy results from degeneration of neurons that produce hypocretin (Hcrt;also known as orexin), no small-molecule brain-penetrable Hcrt receptor agonists currently exist for hypocretin replacement therapy. Current treatments include controlled substances with abuse potential or drugs with other undesirable side effects. In papers just published with scientists from F. Hoffmann- LaRoche, we describe novel, brain-penetrable agonists for Trace Amine-associated Receptor 1 (TAAR1). These compounds cause a dose-dependent increase in wakefulness, reduce REM sleep, and have pro- cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of pathological sleepiness in addition to neuropsychiatric disorders. In this proposal, we will determine the therapeutic efficacy of TAAR1 agonism as a treatment for narcolepsy in proof-of-concept studies using two murine narcolepsy models. First, we will determine whether full and partial TAAR1 agonists promote wakefulness, reduce cataplexy and normalize arousal states in the orexin/ataxin-3 mouse, in which Hcrt neurons have been genetically engineered to degenerate postnatally. Next, we will test these compounds in a novel, inducible model of murine narcolepsy-the orexin/tTA;Tet-O DTA mouse-in which ablation of Hcrt neurons is controlled through the tetracycline transactivator (Tet-off) system to recapitulate the post-pubertal onset of human narcolepsy. In each model, we will compare the efficacy of TAAR1 agonists against the known wake-promoting therapeutic modafinil and anti-cataplectic agent desipramine. We will also compare the dose- response effects of TAAR1 agonism in orexin/ataxin-3 mice with wild-type littermates, and in orexin/tTA;Tet-O DTA mice before and after narcolepsy induction, to test the hypothesis that TAAR1 agonism normalizes arousal states. Discovery of TAAR1 agonists for the treatment of narcolepsy will also advance the development of wake-promoting therapeutics based on modulation of trace amine signaling.

Public Health Relevance

Narcolepsy affects 1 in 2000 people and is characterized by excessive daytime sleepiness, cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and a cluster of other symptoms indicative of a Rapid Eye Movement sleep abnormality. Current treatments include controlled substances with abuse potential or drugs with other undesirable side effects. The goal of our research program is to identify and develop narcolepsy therapeutics that is both wake-promoting and cataplexy-inhibiting. In papers just published with scientists from F. Hoffmann-LaRoche, we describe novel, brain-penetrable agonists for Trace Amine- associated Receptor 1 (TAAR1). These compounds cause a dose-dependent increase in wakefulness and have pro-cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of neuropsychiatric disorders or conditions of pathological sleepiness. In this proposal, we will determine the therapeutic efficacy of TAAR1 agonism as a treatment for narcolepsy-an orphan disease with little pharmaceutical industry interest.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS083639-01
Application #
8565060
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
He, Janet
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$294,478
Indirect Cost
$144,478
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Williams, Rhîannan H; Vazquez-DeRose, Jacqueline; Thomas, Alexia M et al. (2018) Cortical nNOS/NK1 Receptor Neurons are Regulated by Cholinergic Projections From the Basal Forebrain. Cereb Cortex 28:1959-1979
Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S (2017) Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol 152:89-113
Black, Sarah W; Schwartz, Michael D; Chen, Tsui-Ming et al. (2017) Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics. Biol Psychiatry 82:623-633
Schwartz, Michael D; Black, Sarah W; Fisher, Simon P et al. (2017) Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition. Neuropsychopharmacology 42:1305-1314
Black, Sarah Wurts; Kilduff, Thomas S (2016) H1N1 infection of sleep/wake regions results in narcolepsy-like symptoms. Proc Natl Acad Sci U S A 113:476-7
Schwartz, Michael D; Kilduff, Thomas S (2015) The Neurobiology of Sleep and Wakefulness. Psychiatr Clin North Am 38:615-44