TASIMELTEON USE IN TREATING SLEEP ABERRATIONS

Abstract

The invention relates generally to circadian rhythm disorders and, more particularly, to the treatment or prevention of circadian rhythm disorders based on an individual's HCN1 genotype. One aspect of the invention provides a method of treating an individual for delayed sleep time comprising: determining or having determined from a biological sample of the individual that the individual has a GG genotype at the rs12188518 single nucleotide polymorphism (SNP) locus; and administering to the individual once daily before a target bedtime a dose of tasimelteon effective to advance the sleep time of the individual. Other genotypes related with circadian rhythm disorders are CC at rs11248864 and AA at rs72762058.

Claims

1. A method of treating an individual for delayed sleep time comprising: determining or having determined from a biological sample of the individual that the individual has a GG genotype at the rs12188518 single nucleotide polymorphism (SNP) locus; and administering to the individual once daily before a target bedtime a dose of tasimelteon effective to advance the sleep time of the individual.

2. The method of claim 1, wherein the administration is oral.

3. The method of claim 1, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the individual's target bedtime.

4. The method of claim 1, wherein the dose is between about 10 mg and about 100 mg.

5. The method of claim 3, wherein the dose is between about 20 mg and about 50 mg.

6. The method of claim 4, wherein the dose is 20 mg.

7. A method of treating an individual for delayed sleep time comprising: determining or having determined from a biological sample of the individual that the individual has a CC genotype at the rs11248864 single nucleotide polymorphism (SNP) locus; and administering to the individual once daily before a target bedtime a dose of tasimelteon effective to advance the sleep time of the individual.

8. The method of claim 7, wherein the administration is oral.

9. The method of claim 7, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the target bedtime.

10. The method of claim 7, wherein the dose is between about 10 mg and about 100 mg.

11. The method of claim 10, wherein the dose is between about 20 mg and about 50 mg.

12. The method of claim 11, wherein the dose is 20 mg.

13. In a method of treating a patient for delayed sleep time, the improvement comprising: determining or having determined from a biological sample of the patient the patient's genotype at the rs12188518 single nucleotide polymorphism (SNP) locus, the rs11248864 SNP locus, or both; and in the case that the genotype of the patient is GG at the rs12188518 SNP locus, the genotype of the patient is CC at the rs11248864 SNP locus, or both, administering to the patient once daily a dose of tasimelteon effective to advance the patient's sleep time.

14. The improvement of claim 13, wherein the administration comprises an oral dose 0.5 hour to 2 hours before a target bedtime.

15. The improvement of claim 14, wherein the dose is about 10 mg to about 100 mg.

16. The improvement of claim 15, wherein the dose is about 20 mg to about 50 mg.

17. The improvement of claim 16, wherein the dose is about 20 mg.

18. The improvement of claim 13, wherein the dose administered to the patient is greater than would be administered to an individual to advance sleep time not having a genotype indicative of a predisposition to having a delayed sleep time.

19. A method of delaying sleep time or delaying sleep phase in an individual, the method comprising: determining or having determined from a biological sample of the individual that the individual has an AA or AG genotype at the rs12188518 single nucleotide polymorphism (SNP) locus; and administering to the individual at least one hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor.

20. The method of claim 19, wherein the at least one HCN channel inhibitor is selected from a group consisting of: ivabradine, cilobradine, zatebradine, and cesium.

21. A method of delaying sleep time or delaying sleep phase in an individual, the method comprising: determining or having determined from a biological sample of the individual that the individual has a TT or TC genotype at the rs11248864 single nucleotide polymorphism (SNP) locus; and administering to the individual at least one hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor.

22. The method of claim 21, wherein the at least one HCN channel inhibitor is selected from a group consisting of: ivabradine, cilobradine, zatebradine, ZD7299, and cesium.

23. A method of treating an individual determined to have a genotype predictive of an elongated circadian period (tau) based upon the individual having an AA genotype at the rs72762058 single nucleotide polymorphism (SNP) locus, the method comprising: administering to the individual once daily before a target bedtime a dose of tasimelteon effective to shorten the tau of the individual.

24. The method of claim 23, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the target bedtime.

25. The method of claim 23, wherein the dose is about 10 mg to about 100 mg.

26. The method of claim 25, wherein the dose is about 20 mg to about 50 mg.

27. The method of claim 26, wherein the dose is about 20 mg.

28. A method of altering a circadian period (tau) in an individual, the method comprising: determining a genotype of the individual at the rs72762058 single nucleotide polymorphism (SNP) locus; and in the case that the genotype of the individual at the rs72762058 SNP locus is AA, administering to the individual a quantity of tasimelteon effective to decrease the tau of the individual.

29. The method of claim 28, wherein the administration is oral.

30. The method of claim 28, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the individual's target bedtime.

31. The method of claim 28, wherein the dose is between about 10 mg and about 100 mg.

32. The method of claim 31, wherein the dose is between about 20 mg and about 50 mg.

33. The method of claim 32, wherein the dose is 20 mg.

34. A method of treating a patient having a delayed sleep phase who is being treated with a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, the method comprising: administering to the patient once daily a dose of tasimelteon effective to advance the patient's sleep time.

35. The method of claim 34, wherein the HCN channel inhibitor is selected from a group consisting of: ivabradine, cilobradine, zatebradine, ZD7299, and cesium.

36. The method of claim 34, wherein the administration is oral.

37. The method of claim 34, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the individual's target bedtime.

38. The method of claim 34, wherein the dose is between about 10 mg and about 100 mg.

39. The method of claim 38, wherein the dose is between about 20 mg and about 50 mg.

40. The method of claim 39, wherein the dose is 20 mg.

41. In a method of treating an individual for a circadian rhythm disorder, the improvement comprising: determining a genotype of the individual at the rs72762058 single nucleotide polymorphism (SNP) locus; and in the case that the genotype of the individual at the rs72762058 SNP locus is AA, administering to the individual a quantity of tasimelteon effective to shorten a circadian period (tau) of the individual.

42. The method of claim 41, wherein the administration is oral.

43. The method of claim 41, wherein the administration comprises an oral dose 0.5 hour to 2 hours before the individual's target bedtime.

44. The method of claim 41, wherein the dose is between about 10 mg and about 100 mg.

45. The method of claim 44, wherein the dose is between about 20 mg and about 50 mg.

46. The method of claim 45, wherein the dose is 20 mg.

Description

DETAILED DESCRIPTION

[0035] The present invention can be further understood through the following examples.

Example 1

[0036] Chronotype Prediction

[0037] A first whole genome sequencing study is conducted using 316 samples collected as part of a clinical study directed to the effects of abrupt circadian advance, as may be experienced during eastward jet travel, and the ability of tasimelteon to mitigate or eliminate those effects. Participants in that study are healthy, sighted individuals not known to be suffering from a circadian rhythm disorder or sleep disorder.

[0038] More than 400 single nucleotide polymorphisms (SNPs) in linkage disequilibrium are found. Among the SNPs that are identified in this study, rs121888518, located within the HCN1 gene on chromosome 5, is found to be predictive of evening chronotype when compared to individuals' Morningness-Eveningness Questionnaire (MEQ) scores. Specifically, individuals with a GG genotype at the rs121888518 SNP locus are significantly more likely to be classified as having an evening chronotype based on MEQ score. This association is persistent in a binary analysis (logistic regression) and when using alternative morningness-eveningness questionnaires. Expression quantitative trait locus (eQTL) analysis indicates a significant result (1.6.Math.10.sup.9) for the rs121888518 SNP

[0039] These results are consistent with a mechanism of action by which individuals exhibit an evening chronotype.

[0040] The HCN1 channel is responsible for feedback on the rods, regulating the dynamic range of light reactivity under dim or intermediate light conditions. Proper cone vision under mesopic conditions requires rapid adaptational feedback modulation of rod output via the HCN1 channels. When these channels are absent or inhibited, sustained rod responses following bright light exposure saturate the retinal network, resulting in a loss of downstream cone signaling.

[0041] The improper functioning of this feedback system in an individual may result in rod saturation, even in dim light. This may result in a misperception of light conditions and a consequent circadian delay, experienced as a sleep aberration, which may include delayed sleep time.

[0042] Thus, resetting the circadian period of an individual with a genetic predisposition to having an evening chronotype (e.g., GG genotype at the rs121888518 SNP locus) provides an avenue to eliminate or ameliorate the consequences of such a sleep aberration. Administering to such an individual a dose of tasimelteon before a target bedtime operates to advance the sleep time in the individual, thereby treating the sleep aberration.

[0043] Another SNP, rs11248864, located on chromosome 16, similarly exhibits a significant correlation (p<10.sup.−8) with chronotype. Specifically, individuals having a CC genotype at the rs11248864 SNP locus are significantly more likely to be classified as having an evening chronotype based on MEQ score (eQTL=1.3.Math.10.sup.8).

[0044] The rs11248864 SNP is located within the Ubiquitin Conjugating Enzyme E2 I (UBE2I) gene. The UBE2I enzyme directly interacts with transcriptional repressor BHLHE40 and is potentially of direct relevance to the input and output of the circadian clock. The UBE2I region is also a significant eQTL for brain-specific angiogenesis inhibitor (BAIAP3), which in turn likely plays a role in hypothalamic neuronal firing by modulating gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission and is highly expressed in the pituitary.

[0045] As noted above, resetting the circadian period of an individual with a genetic predisposition to having an evening chronotype provides a method to eliminate or ameliorate the consequences of such a sleep aberration. Thus, administering to such an individual (e.g., one having a CC genotype at the rs11248864 SNP locus) a dose of tasimelteon before a target bedtime operates to advance the sleep time in the individual, thereby treating the sleep aberration.

[0046] This mechanism of action also suggests a method by which to delay sleep time in an individual. For example, an individual not predicted to have an evening chronotype (e.g., an individual having an AA or AG genotype at the rs12188518 SNP locus or a TT or TC genotype at the rs11248864 SNP locus) may be administered an HCN channel inhibitor in an amount effective to induce in such an individual a saturation of the rods under dim or intermediate light conditions, resulting in a delayed sleep time. Suitable HCN inhibitors include, for example, ivabradine, cilobradine, zatebradine, or cesium.

Example 2

[0047] HCN1 and Prolonged Tau

[0048] A second whole genome sequencing study is conducted of 174 totally blind individuals with Non-24-Hour Sleep-Wake Disorder (Non-24). Non-24 is a circadian rhythm disorder in which the master body clock runs either slightly shorter or, more commonly, slightly longer than 24 hours.

[0049] Within this group, an association is found between HCN1 variants and circadian period length (tau) as calculated from the measurement of urinary 6-sulphatoxymelatonin (aMT6s) rhythms, aMT6s being the major metabolite of melatonin. Specifically, the minor allele of the SNP rs72762058, representing a G-to-A mutation at position 45467426, shows a significant association with longer tau. Individuals with this mutation have a mean tau of 24.71 hours, 12 minutes longer than those not having the minor allele.

[0050] Thus, shortening the tau of an individual shown to have a genetic predisposition to having a long tau provides a method for treating circadian rhythm and sleep aberrations associated with a long tau. Administering to such an individual an effective amount of tasimelteon operates to shorten the individual's tau, resulting in elimination or amelioration of the circadian rhythm or sleep aberration.

[0051] The description of the present disclosure is presented for purposes of illustration and description but is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the disclosure.