The invention provides compositions and methods for treatment of sleep disorders. Such methods entail administering to the patient a therapeutically effective dosage regime of an agonist of a hypocretin 1 (Hcrt-1) receptor to a peripheral tissue of the patient, and monitoring the condition of the patient responsive to the treatment, wherein the monitoring indicates a reduction in excessive daytime sleepiness (EDS) and an improvement in nighttime sleep consolidation and architecture. The methods are particularly useful for prophylactic and therapeutic treatment of one or more sleep disorders in a patient.

Description of the Invention

SUMMARY OF THE INVENTION

In one aspect, the invention provides methods of treating a sleep disorder in a patient. Some methods entail administering to the patient a therapeutically effective dosage regime of an agonist of a hypocretin receptor. In some such methods, the agonist is hypocretin-1 or hypocretin-2. In some such methods, the agonist is a natural human hypocretin-1 or hypocretin-2. In some such methods, the therapeutically-effective dosage regime is administered to a peripheral tissue of the patient, whereby the agonists crosses the blood brain barrier of the patient. In some such methods, the patient experiences a reduction in excessive daytime sleepiness responsive to the administering. In some such methods, the patient experiences an improvement in nighttime sleep consolidate and architecture responsive to the treatment. In some methods, monitoring the condition of the patient responsive to administering the therapeutically effective dosage regime is performed. In some such methods, the monitoring indicates a reduction in excessive daytime sleepiness and an improvement in nighttime sleep consolidation and architecture.

In another aspect, the invention provides methods of treating a sleep disorder in a patient that entail administering to the patient a therapeutically effective dosage regime of hypocretin 1 (Hcrt-1) to a peripheral tissue of the patient, and monitoring the condition of the patient responsive to the treatment. In some such methods, the monitoring indicates a reduction in excessive daytime sleepiness (EDS) and an improvement in nighttime sleep consolidation and architecture. In some such methods, the patient is human.

In some methods, the sleep disorder is narcolepsy, cataplexy, REM sleep behavior disorder, sleep apnea, and insomnia. In some such methods, the hypocretin 1 is free of a label. In some such methods, the therapeutically effective dosage regime is administered after diagnosis of one or more sleep disorders. In some such methods, the hypocretin 1 (Hcrt-1) is administered together with a pharmaceutically acceptable carrier as a pharmaceutical composition.

For treatment of patients susceptible to or suffering from one or more sleep disorders, the dosage in the regime is separated by at least 12 hours. In some treatment regimes, the dosage in the regime is separated by at least 24 hours. In some such treatment regimes, the dosage is 0.3 to about 10 .mu.g/kg of hypocretin 1 (Hcrt-1).

The Hcrt-1 is typically administered by intravenous infusion, transdermal delivery, intramuscular delivery, subcutaneous delivery, oral delivery, or by inhalation. In some such methods, Hcrt-1 is administered by intravenous infusion. In other such methods, Hcrt-1 is administered by oral delivery. Typically, the patient is monitored following administration to assess the effects of treatment. Some such monitoring includes conducting a nocturnal polysomnogram (PSG), Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (EPS) questionnaire, Maintenance of Wakefulness Test (MWT), pupilography, electroencephalograms, electroencephalographic spectral analysis, actigraphy, or maintaining a log of incidence of cataplexy including their number, severity and duration. Other methods of monitoring include conducting immune or histological assays to determine the presence or absence of neurodegeneration, nerve cell death, T cell infiltration, B cell infiltration, monocytic infiltration, apoptosis, or necrosis.

In another aspect, the invention provides methods of diagnosing a sleep disorder in a patient. Such methods entail assaying for the presence of detectable levels of Hcrt-1 or hypocretin 2 (Hcrt-2) in the cerebrospinal fluid or blood serum of a patient.

In another aspect, the invention provides pharmaceutical compositions for treating a sleep disorder in a patient, comprising a therapeutically effective dosage of Hcrt-1 and a pharmaceutically acceptable carrier to reduce daytime sleepiness and improve nighttime sleep consolidation and architecture.

The invention further provides methods of treating schizophrenia in a patient. Such methods entail administering to the patient a therapeutically effective dosage regime of Hcrt-1 to a peripheral tissue of the patient, and monitoring the condition of the patient responsive to the treatment, wherein the monitoring indicates a reduction in excessive daytime sleepiness (EDS) and an improvement in nighttime sleep consolidation and architecture.

The invention further provides methods of treating Alzheimer's in a patient. Such methods entail administering to the patient a therapeutically effective dosage regime of Hcrt-1 to a peripheral tissue of the patient, and monitoring the condition of the patient responsive to the treatment, wherein the monitoring indicates a reduction in excessive daytime sleepiness (EDS) and an improvement in nighttime sleep consolidation and architecture.

The invention further provides methods of treating depression in a patient. Such methods entail administering to the patient a therapeutically effective dosage regime of Hcrt-1 to a peripheral tissue of the patient, and monitoring the condition of the patient responsive to the treatment, wherein the monitoring indicates a reduction in excessive daytime sleepiness (EDS) and an improvement in nighttime sleep consolidation and architecture.

DETAILED DESCRIPTION

General

The invention is premised, in part, on the result that administration of hypocretin-1 (Hcrt-1) produces an increase in activity level, longer waking periods, a decrease in REM sleep without change in nonREM sleep, reduced sleep fragmentation and/or a dose dependent reduction in cataplexy in canines with a hereditary form of narcolepsy. These and other results described in the Examples section lead to the conclusion that repeated administration of Hcrt-1 led to consolidation of waking and sleep periods and to a complete loss of cataplexy for periods of three or more days after treatment in animals that were never asymptomatic under control conditions. A particularly striking finding was that Hcrt-1 administration caused a consolidation of both sleep and waking states. The invention provides therapeutically effective dosage regimes for administering Hcrt-1 to patients having sleep disorders. Furthermore, the treatment regimes can employ similar dosages, routes of administration and frequency of administration to those used in treating canine narcoleptics. Although practice of the present methods is not dependent on an understanding of mechanism, the results provided by the application suggest that Hcrt-1 provides correlated improvements in cataplexy, waking duration and sleep continuity.

Because the daytime sleep deficit and related symptoms in narcolepsy so closely resemble the sleep deficit and other symptoms in other sleep disorders (e.g., REM sleep behavior disorder, restless legs syndrome, hypersomnia, insomnia, disrupted sleep in the elderly and other sleep disorders) characterized by daytime sleepiness, administration of a therapeutically effective dosage regime of Hcrt-1 is expected to reduce excessive daytime sleepiness and improve nighttime sleep consolidation and architecture in patients with these sleep disorders.

III. Sleep Disorders

A. General

There are a number of disorders that disturb sleep and cause patients to seek medical care (see, e.g., Chokroverty, S. (ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, 2.sup.nd edition, Butterworth Heinemann, Boston, Mass. U.S.A. 1999; Aldrich, M., Sleep Medicine, Oxford University Press, New York, N.Y. U.S.A. 1999; these references and all references cited therein are herein incorporated by reference). These include narcolepsy, REM sleep behavior disorder, periodic movements during sleep, restless legs syndrome, circadian rhythm disorder, sleep apnea, hypersomnia and insomnia. Other medical disorders including Alzheimer's, depression and schizophrenia can also affect sleep. In these cases, the sleep abnormality can have a role in the etiology of the disease or can only be symptomatic. The sleep disorders described below can be treated by the methods described herein.

B. Narcolepsy

Narcolepsy is a chronic neurological disorder characterized by recurring episodes of sleep or sleepiness during the day, and often disrupted nocturnal REM sleep (see, e.g., Chokroverty, S. (ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, 2.sup.nd edition, Butterworth Heinemann, Boston, Mass. U.S.A. 1999; Aldrich, M., Sleep Medicine, Oxford University Press, New York, N.Y. U.S.A. 1999). Symptoms of narcolepsy include abnormal sleep features, overwhelming episodes of sleep, excessive daytime somnolence (EDS), abnormal REM sleep, hypnagogic and hypnopompic hallucinations, disturbed nocturnal sleep, cataplexy, and sleep paralysis. EDS includes daytime sleep attacks, which may occur with or without warning; persistent drowsiness, which may continue for prolonged periods of time; and "microsleeps" or fleeting moments of sleep intruding into the waking state. Cataplexy is usually an abrupt and reversible decrease or loss of muscle tone most frequently elicited by emotion. It can involve a limited number of muscles or the entire voluntary musculature except the extraocular muscles and to some extent the diaphragm. Typically, the jaw sags, the head falls forward, the arms drop to the side, and/or the knees unlock, or the cataplectic human may fall completely on the ground. The duration of a cataplectic attack, partial or total, usually varies from a few seconds to thirty minutes. Attacks can be elicited by emotion, stress, fatigue, exercise or heavy meals. Sleep paralysis is an experience that occurs when an individual falls asleep or awakens, and is very akin to complete cataplectic episodes. Patients can find themselves suddenly unable to move, speak, open their eyes, or even breathe deeply. Hypnagogic hallucinations often involve vision, and the manifestations usually consist of simple forms (i.e., colored circles, parts of objects) that may be constant in size or changing, or may be quite complex in their scenario. Auditory hallucinations are also common and can range from a collection of sounds to an elaborate speech or melody. Hallucinations at sleep onset can involve elementary cenesthopathic (abnormal) sensations (e.g., prickling, rubbing, light touching), changes in location of body parts, or feelings of levitation or extracorporeal experiences. Patients having cataplexy without EDS are said to have isolated cataplexy. Other symptoms of narcolepsy besides EDS may or may not be present in such patients. Narcolepsy and isolated cataplexy are classified as separate indications by FDA. Nevertheless, this classification does not imply a separate basis. Both indications can be treated by the methods described in the application.

C. REM Sleep Behavior Disorder

REM sleep behavior disorder (RBD) is characterized by the intermittent loss of REM sleep electromyographic (EMG) atonia and by the appearance of elaborate motor activity associated with dream mentation.

Punching, kicking, leaping, and running from the bed during attempted dream enactment are frequent manifestations and usually correlate with the reported imagery.

Medical attention is often sought after injury has occurred to either the person or a bed partner. Occasionally, a patient may present because of sleep disruption. Because RBD occurs during REM sleep, it typically appears at least 90 minutes after sleep onset. Violent episodes typically occur about once per week but may appear as frequently as four times per night over several consecutive nights.

An acute, transient form can accompany REM rebound during withdrawal from alcohol and sedative-hypnotic agents. Drug-induced cases have been reported during treatment with tricyclic antidepressants and biperiden.

There can be a prodromal history of sleep talking, yelling, or limb jerking. Dream content can become more vivid, unpleasant, violent, or action-filled coincident with the onset of this disorder. Symptoms of excessive daytime sleepiness can appear if sufficient sleep fragmentation exists.

Some patients with this disorder also have narcolepsy, suggesting that there are common neurological causes of these disorders and that administration of a therapeutically effective dosage regime of Hcrt-1 can be effective for RBD as well.

D. Periodic Leg Movements in Sleep (PLMS) and Restless Legs Syndrome (RLS)

Periodic Leg Movements in Sleep (PLMS) is a sleep disorder that consists of periodic movements of the legs, feet, and/or toes during sleep. People with PLMS are often not aware of these movements, and often complain of several symptoms, including: insomnia; excessive daytime sleepiness (EDS); frequent awakenings from sleep, or unrefreshing sleep. Since EDS is associated with narcolepsy described above and administration of Hcrt-1 is effective in treating narcolepsy, PLMS can also be treated with a therapeutically effective dosage regime of Hcrt-1.

PLMS is frequently associated with a sleep disorder referred to as Restless Legs Syndrome (RLS). RLS is a disorder of the central nervous system that is characterized by unusual sensations in the legs and an overwhelming urge to move the legs while resting or attempting to fall asleep. Approximately 2% of the population in the U.S. suffer from RLS. Not all patients with PLMS also have RLS; however, most patients with RLS have PLMS. RLS is occasionally associated with pregnancy, anemia, or diabetes. Symptoms of RLS also can include: creeping or crawling sensations in the legs; an irresistible urge to move the affected extremity; relief of the symptoms by walking; a worsening of the symptoms when the afflicted person is at rest, particularly during the afternoon and evening hours. It has recently been reported that canine narcoleptics frequently have PLMS. Human narcoleptics can also have PLMS.

Since RLS is linked to narcolepsy and narcolepsy is caused by a deficiency in Hcrt release or in the response to Hcrt, RLS can be treated by administering a therapeutically effective dosage regime of Hcrt-1.

E. Circadian Rhythm Disorder

Circadian rhythm refers to a person's dark-light or sleep-wake pattern during a 24-hour cycle. Over 25 million Americans work the night shift or have nontraditional working schedules. Approximately 70% of these people suffer from Circadian Rhythm Disorder, an interruption in the biologic clock which results in a disruption in the regular intervals of sleeping and waking during a 24 hour-period. Circadian rhythm disorder can take different forms.

One form is Delayed Sleep Phase Syndrome (DSPS), in which the person goes to sleep later and, consequently, rises later than usual. This often interferes with normal work or school schedules. Symptoms can include: inadequate amounts of sleep; inability to fall asleep and difficulty awakening; impaired work performance, with chronic lateness or absences, difficulty concentrating, memory lapses.

Delayed sleep-phase syndrome (DSPS) is marked by: (1) sleep-onset and wake times that are intractably later than desired, (2) actual sleep-onset times at nearly the same daily clock hour, (3) little or no reported difficulty in maintaining sleep once sleep has begun, (4) extreme difficulty awakening at the desired time in the morning, and (5) a relatively severe to absolute inability to advance the sleep phase to earlier hours by enforcing conventional sleep and wake times. Typically, the patients complain primarily of chronic difficulty in falling asleep until between 2 a.m. and 6 a.m. or difficulty awakening at the desired or necessary time in the morning to fulfill social or occupational obligations. Daytime sleepiness, especially in the morning hours, occurs variably, depending largely on the degree of sleep loss that ensues due to the patient's attempts to meet his or her social obligations by getting up "on time." When not obliged to maintain a strict schedule (e.g. on weekends or during vacations), the patient sleeps normally but at a delayed phase relative to local time.

Patients with DSPS are usually perplexed that they cannot find a way to fall asleep more quickly. Their efforts to advance the timing of sleep onset (early bedtime, help from family or friends in getting up in the morning, relaxation techniques, or the ingestion of hypnotic medications) yield little or no effect at all in aiding sleep onset and may only aggravate the daytime symptoms of difficulty awakening and sleepiness. Chronic dependence on hypnotics or alcohol for sleep is unusual but, when present, complicates the clinical situation. More commonly, patients give a history of having tried multiple sedating agents, which were abandoned because of only transient efficacy.

Another form of circadian rhythm disorder is Advanced Sleep Phase Syndrome (ASPS), in which the person experiences excessive sleepiness in the early evening and has a very early awakening time. Patients with ASPS often complain about difficulty staying awake in evening social situations and insomnia at the end of the sleep period, with early morning awakening.

Advanced sleep-phase syndrome is marked by a person's intractable and chronic inability to delay the onset of evening sleep or extend sleep later into the morning hours by enforcing more conventional social sleep and wake times. The major presenting complaint can concern either the inability to stay awake in the evening, or early morning awakening insomnia, or both. Unlike other sleep maintenance disorders, the early morning awakening occurs after a normal amount of otherwise undisturbed sleep. In pure cases, there is no major mood disturbance during the waking hours. Unlike in other cases of excessive sleepiness, daytime school or work activities are not affected by somnolence. However, evening activities are routinely curtailed by the need to retire much earlier than the social norm. Typical sleep-onset times are between 6 p.m. and 8 p.m., and no later than 5 a.m. These sleep-onset and wake times occur despite the patient's best efforts to delay sleep to later hours.

Negative personal or social consequences can occur due to leaving activities in the early to mid-evening hours in order to go to sleep. Attempts to delay sleep onset to a time later than usual can result in falling asleep during social gatherings, or can have more serious consequences, such as drowsiness or falling asleep while driving in the evening. Afflicted individuals who attempt to work evening or night shifts would presumably have marked difficulty staying awake during the evening and early morning hours. If patients are chronically forced to stay up later for social or vocational reasons, the early-wakening aspect of the syndrome could lead to chronic sleep deprivation and daytime sleepiness or napping.

The potent and long lasting arousing effects of Hcrt-1 are likely to be effective in entraining patients to the desired circadian phase. The phase achieved would be dependent upon the time of drug administration.

F. Sleep Apnea

Sleep Apnea is a sleep disorder in which a person repeatedly stops breathing for short periods during sleep, often without being aware of the cessations of breath. An obstructed airway is the most common cause of the apnea. Approximately 12 million Americans have sleep apnea, which is more common in men than in women. Symptoms can include: brief interruption of breathing periodically during sleep; extremely loud snoring that is interrupted by pauses and gasps; choking sensations during sleep; falling asleep at inappropriate times during the day, such as while driving, working, or talking; awakening with headaches in the morning.

In sleep apnea, relaxation of the muscles of the tongue and the soft palate at the base of the throat, allows the breathing passage to collapse in individuals with a narrow airway. Although chest movements may continue, no air flows into the lungs and oxygen levels in the blood decrease. When blood oxygen levels fall too low, the person briefly wakes to take a breath. This gasping breath can produce a loud, characteristic snort. The cycle of sleeping, airway collapsing, waking, and sleeping repeats, often hundreds of times in a night. Individuals with sleep apnea do not remember these brief awakenings and believe they slept through the night. However, the interrupted sleep leaves the individual exhausted in the morning and sleepy throughout the day. If left untreated, sleep apnea may also cause cardiovascular problems and greatly shorten life span.

Central sleep apnea syndrome is characterized by a cessation or decrease of ventilatory effort during sleep and is usually associated with oxygen desaturation.

This disorder is usually associated with a complaint of insomnia with an inability to maintain sleep; however, excessive sleepiness can also occur. Several awakenings during the course of the night usually occur, sometimes with a gasp for air for evaluation because of observations by a concerned bed partner. Feelings of daytime tiredness, fatigue, and sleepiness are common. Central sleep apnea syndrome can have a few associated obstructive apneas and episodes of hypoventilation; however, the predominant respiratory disturbance consists of central apneic episodes.

Snoring can occur but is not prominent. The hemodynamic complications of this syndrome can include the development of cardiac arrhythmias, pulmonary hypertension, and cardiac failure. These hemodynamic findings can reflect a primary disorder of the cardiovascular system that leads to the development of the apnea. Difficulties with memory and other cognitive functions can result from the excessive sleepiness. Headaches upon awakening are common in patients with severe alteration of blood gases during sleep. Depressive reactions can also occur.

The invention provides methods for treating the excessive daytime tiredness, fatigue, and sleepiness associated with sleep apnea by administering a therapeutically effective dosage regime of Hcrt-1.

G. Hypersomnia

Idiopathic hypersomnia is a sleep disorder that is associated with a normal or prolonged major sleep episode and excessive sleepiness consisting of prolonged (1 to 2 hour) sleep episodes of nREM sleep.

Idiopathic hypersomnia can be characterized by a complaint of constant or recurrent excessive daytime sleepiness, typically with sleep episodes lasting 1 or more hours in duration. It can be enhanced in situations that allow sleepiness to become manifest, such as reading or watching television in the evening. The major sleep episode can be prolonged, lasting more than 8 hours. The capacity to arouse the subject can be normal, but some patients report great difficulty waking up and experience disorientation after awakening.

Some patients complain of paroxysmal episodes of sleepiness culminating in sleep attacks, as in narcoleptic patients described above. Most often these attacks are preceded by long periods of drowsiness. Naps are usually longer than in narcolepsy or sleep apnea, and short naps are generally reported as being nonrefreshing. Often as disabling as narcolepsy, idiopathic hypersomnia has an unpredictable response to stimulants such as the amphetamines and methylphenidate hydrochloride. These patients often report more side effects, such as tachycardia or irritability, and the use of stimulants tend to exacerbate the associated symptoms of headache.

Associated symptoms suggesting dysfunction of the autonomic nervous system are not uncommon. They include headaches, which may be migrainous in quality; fainting episodes (syncope); orthostatic hypotension; and, most commonly, peripheral vascular complaints.

The invention provides methods for treating the long periods of drowsiness that accompanies hyposomnia by administering a therapeutically effective dosage regime of Hcrt-1.

H. Insomnia

Insomnia is the difficulty in initiating or maintaining sleep. This term is employed ubiquitously to indicate any and all gradations and types of sleep loss. Insomnia is generally characterized by disrupted nighttime sleep, with frequent arousals, reduced or absent stage 4 sleep and in some cases frequent daytime napping.

Chronically poor sleep in general leads to decreased feelings of well-being during the day. There is a deterioration of mood and motivation, decreased attention and vigilance, low levels of energy and concentration, and increased fatigue.

Mild insomnia is described as an almost nightly complaint of an insufficient amount of sleep or not feeling rested after the habitual sleep episode. It is accompanied by little or no evidence of impairment of social or occupational functioning. Mild insomnia often is associated with feelings of restlessness, irritability, mild anxiety, daytime fatigue, and tiredness.

Moderate insomnia can be described as a nightly complaint of an insufficient amount of sleep or not feeling rested after the habitual sleep episode. It can be accompanied by mild or moderate impairment of social or occupational functioning. Moderate insomnia always is usually associated with feelings of restlessness, irritability, anxiety, daytime fatigue, daytime sleepiness and tiredness.

Severe insomnia can be described as a nightly complaint of an insufficient amount of sleep or not feeling rested after the habitual sleep episode. It can be accompanied by severe impairment of social or occupational functioning. Severe insomnia is usually associated with feelings of restlessness, irritability, anxiety, daytime fatigue, and tiredness.

The invention provides methods for treating the daytime fatigue and daytime sleepiness that accompanies insomnia by administering a therapeutically effective dosage regime of Hcrt-1.

I. Other Disorders

1. Alzheimer's Depression

Alzheimer's is a degenerative disease causing diffuse neurodegeneration and resultant loss of memory, reasoning ability and ability to care for oneself. In its later stages, disorientation, fragmented sleep and insomnia manifest as "sundowning" or nighttime wandering behavior are characteristic and are frequent cause of institutionalization. Daytime sleepiness is also a correlate of Alzheimer's. The daytime sleepiness, nighttime sleep disruption and neurodegeneration all overlap with what is known about the pathophysiology and anatomy of narcolepsy.

A degeneration of the hypocretin system or a deficiency of hypocretin release may be linked to the occurrence of these symptoms as it is in narcolepsy. The invention provides methods for treating Alzheimer's by administering a therapeutically effective dosage regime of Hcrt-1.

2. Depression

Depression is characterized by a pervasive feeling of sadness or helplessness, suicidal impulses and a loss of interest in previously pleasurable activities. It is also frequently characterized by daytime sleepiness, short sleep latency and disrupted nighttime sleep. A shortened latency to REM sleep is characteristic as the case in narcolepsy. These sleep disturbances are strikingly similar to those seen in narcolepsy. Narcoleptics are significantly more likely than age and sex matched controls to be depressed with some studies calculating that nearly 50% of narcoleptics are depressed.

This overlap of specific sleep abnormalities and psychological manifestations between narcolepsy and depression indicates that common mechanisms must link these disorders. Therefore, the invention provides methods for treating depression by counteracting the short REM sleep latency and daytime sleepiness and by consolidating nighttime sleep by administering a therapeutically effective dosage regime of Hcrt-1.

3. Schizophrenia

Schizophrenia is a group of severe emotional disorders characterized by misinterpretation and retreat from reality, delusions, hallucinations, inappropriate emotional affect, and withdrawn, bizarre or regressive behavior.

Several aspects of schizophrenia overlap with narcolepsy (Siegel et al., 1999, J. Neuroscience 19: 48-257). Narcolepsy and schizophrenia may co-exist in patients. The characteristic hallucinations of schizophrenia can resemble the hypnagogic hallucinations of narcolepsy. Age of onset is similar in narcolepsy and schizophrenia, typically in the second or third decade for both diseases. Both diseases are characterized by degenerative changes in the limbic system, a region heavily innervated by hypocretin neurons. REM sleep at sleep onset is also characteristic of both disorders. Finally disrupted nighttime sleep and daytime sleepiness can be characteristic of schizophrenia, as in narcolepsy.

These similarities of sleep and behavior suggest similar underlying pathology in these two disorders. Therefore the invention provides methods for treating schizophrenia by administering a therapeutically effective regime of Hcrt-1.

IV. Patients Amenable to Treatment

Patients amenable to treatment include patients who are presently asymptomatic but who are at risk of developing a sleep disorder, e.g., symptomatic narcolepsy or isolated cataplexy, at a later time. Such individuals include those having relatives who have experienced a sleep disorder, and those whose risk is determined by analysis of genetic or biochemical markers, or by biochemical methods. Other patients amenable to treatment can include patients wherein the administration of the treatment ameliorates, prevents, or reduces one or more symptoms of one or more sleep disorders within hours or months of treatment. Patients to receive treatment can also include individuals who are not diagnosed with any sleep disorder.

Genetic markers of risk for developing a particular sleep disorder have been determined. For example, genetic markers of risk for developing narcolepsy include the presence of the HLA allele, HLADQB1*0602. The HLA-DQB1*0602 allele has also been linked to subclinical abnormal nocturnal REM sleep and increased daytime sleepiness in normal subjects as well as certain schizophrenia subtypes (see, e.g., Mignot, E., et al., Sleep (1999) 22(3): 347-352; Cadieux, R., et al., J. Clin. Psychol. (1985) 46: 191-193; Douglass, A., et al., J. Nerv. Ment. Dis. (1991) 179: 12-17; these references and all references cited therein are herein incorporated by reference). The presence or absence of HLA-DQB1*0602 can be determined by standard procedures (see, e.g., Mignot, E., et al., Sleep (1999) 22(3): 347-352, U.S. Pat. Nos. 5,908,749, 5,565,548, 5,541,065, 5,196,308; these references are herein incorporated by reference. Other markers include a mutation or deletion in any Hypocretin (Orexin) Receptor gene, the prepro-Hypocretin (Orexin) gene itself, or in the Hypocretin (Orexin) Receptor 1 or Hypocretin (Orexin) Receptor 2 gene. Additional risk factors for narcolepsy and/or cataplexy include having Niemann-Pick disease type C or Norrie's disease.

Biochemical markers of risk can include a defect in the proteolytic processing of the prepro-orexin precursor of the known hypocretin (orexin) molecules, or in the posttranslational modification mechanism that results in the abnormal production of Hcrt-1 (orexin-A) and Hcrt-2 (orexin-B) molecules. Other biochemical markers of risk for narcolepsy include autoantibodies or activated lymphocytes in the blood in individuals free of other immune-mediated and/or neoplastic diseases, or the presence of specific autoantibodies in individuals with or without other immune-mediated and/or neoplastic diseases. The presence of such markers in asymptomatic individuals signifies that the processes leading to narcolepsy or cataplexy is almost certainly underway, although has not yet progressed so far as to produce symptoms.

In asymptomatic individuals, treatment of sleep disorders can begin at any age including antenatally, or at birth. For example, in narcolepsy, treatment is usually begun before an individual is 45 years old because if an individual has not developed narcolepsy or isolated cataplexy by that time, he or she probably will not do so at all. If a biochemical marker of disease, such as an autoantibody or activated T cell is detected, treatment should usually begin shortly thereafter. If the likelihood of developing a sleep disorder, such as narcolepsy and or cataplexy is based on relatives having the disease or detection of a genetic marker, treatment can also be administered shortly after identification of these risk factors, or shortly after diagnosis. Alternatively, an individual found to possess a genetic marker can be left untreated but subjected to regular monitoring for biochemical or symptomatic changes without treatment. The decision whether to treat immediately or to monitor symptoms depends in part on the extent of risk predicted by the genetic marker(s) found in the individual for a particular sleep disorder. Once begun, a therapeutically effective dosage regime of Hcrt-1 is typically continued at intervals for a period of a week, a month, three months, six months or a year. In some patients, treatment is administered for up to the rest of a patient's life. Treatment can generally be stopped if a biochemical risk marker disappears. In veterinary patients, such as dogs having a hereditary form of narcolepsy, treatment is usually begun at anytime between birth to five months of age.

Other individuals amenable to treatment show or have shown behavioral symptoms of a sleep disorder (i.e., symptomatic patients) (see, e.g., Chokroverty, S. (ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects, 2.sup.nd edition, Butterworth Heinemann, Boston, Mass. U.S.A. 1999; Aldrich, M., Sleep Medicine, Oxford University Press, New York, N.Y. U.S.A. 1999). Such symptoms can be detected by any of the techniques described below. In addition, symptomatic patients often have biochemical or genetic risk factors as described for asymptomatic individuals. In symptomatic patients, treatment usually begins at or shortly after diagnosis of symptoms. Treatment is typically continued at intervals for a week, a month, six months, a year or up to the rest of the patient's life. Typically, the patient's symptoms are monitored. If monitoring indicates a sustained reduction or elimination of symptoms for a period of at least a month, and preferably at least three months, treatment can be terminated or reduced in dosage. Monitoring is continued and treatment is resumed if symptoms reappear or worsen. If treatment causes no significant amelioration of symptoms in a patient for a period of at least six months, and typically at least one year, or if the side effects of the treatment are intolerable to a patient, then treatment can be discontinued.
 

Claim 1 of 18 Claims

1. A method of treating a patient having narcolepsy or cataplexy comprising: peripherally administering a therapeutically effective dosage regime of hypocretin-1 to the patient in need thereof, whereby the hypocretin-1 crosses the blood brain barrier of the patient and thereby treats the narcolepsy or cataplexy in the patient.

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