Challenges in the development of therapeutics for narcolepsy

Abstract

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy—a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy.

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

“…Because cataplexy occurrence varies widely between narcolepsy models (e.g., Veh groups in Figure 5A-D ) as well as among mice of the same genotype (46), data from Alm-pretreated Atax mice and DTA Dox(−) mice were pooled to assess correlations between cataplexy density (number of cataplexy bouts per minutes awake) after Veh vs. the therapeutic change from Veh post-dosing with RO5263397 (0.3-3 mg/kg), RO5256390 (1-10 mg/kg) and Des (5 mg/kg) ( Figure 5E-F ). Pearson product-moment correlations revealed that, as basal cataplexy levels increased (measured as cataplexy density after Veh treatment), cataplexy density after drug treatment decreased for RO5263397 (0.3, 1, 3 mg/kg) ( r (14)=−0.89, −0.62, −0.77, respectively, all P <0.01), RO5256390 (1, 3, 10 mg/kg) ( r (14)=−0.97, −0.74, −0.82, respectively, all P <0.01) and Des (5 mg/kg) ( r (14)=−0.92, P <0.01).…”

“…Suppression of REM sleep is a characteristic of many anticataplectic medications (46). Although both RO5263397 and RO5256390 were effective in reducing cataplexy, RO5263397 was more effective in reducing REM sleep in the Atax narcolepsy model ( Figure 3I ).…”

“…Drugs were prepared as described above using 1.25% hydroxypropyl methyl cellulose/0.1% dioctyl sodium sulfosuccinate in water (w/w) as the Veh. Doses (37, 41, 45, 46) were delivered at 10 mL/kg final volume i.p. (Alm) or p.o.…”

“…Therefore, Atax and DTA mice were dosed at ZT12.5 (ZT0=3:00) in a counter-balanced crossover design with RO5263397 (0.3, 1, 3 mg/kg), RO5256390 (1, 3, 10 mg/kg), Des (5 mg/kg), Mod (100 mg/kg), or Veh. Desipramine was used as a positive control for cataplexy reduction (46) while Mod, an FDA-approved medication for EDS, served as a positive control for wake promotion (45). To increase the occurence of cataplexy, Atax mice were pre-dosed on experimental days with a non-sedating dose of Alm (30 mg/kg) at ZT12 (41, 42).…”

Rapid, noninvasive, and unsupervised detection of sleep/wake using piezoelectric monitoring for pharmacological studies in narcoleptic mice

“…Like their human counterparts, Atax mice experience degeneration of wakepromoting orexin (also known as hypocretin) neurons which leads to cataplexy (a sudden, reversible loss of muscle tone and REM-sleep like EEG) and/or increased sleep propensity at times of day when wakefulness would otherwise predominate (18). Although Atax mice exhibit cataplexy that is readily identifiable according to EEG/EMG-dependent consensus criteria (19), high inter-individual variability in cataplexy occurrence presents a challenge to sort mice for inclusion in studies with cataplexy reduction as an endpoint (20). Currently, there is no prescreening method prior to EEG/EMG studies for sorting mice that are highly symptomatic for narcolepsy.…”