Methods to treat diabetes and related conditions based on polymorphisms in the tcf-1 gene

• US 20050042614A1
• Filed: 10/30/2002
• Published: 02/24/2005
• Est. Priority Date: 10/31/2001
• Status: Abandoned Application

• Current Assignee: Christian Nicolas Lavedan, Milhael Hristos Polymeropoulos, Thomas Edward Hughes
• Original Assignee: Christian Nicolas Lavedan, Milhael Hristos Polymeropoulos, Thomas Edward Hughes
• Inventors: Polymeropoulos, Milhael Hristos, Hughes, Thomas Edward, Lavedan, Christian Nicolas
• Application Number:
  US10/493,885
• Publication Number:
  US 20050042614A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

This invention relates to the use of the novel association between the 483 A>G single nucleotide polymorphism of the TCF1 gene and the clinical response to glycemic control agents, such as DPPIV inhibitors, in patients with disorders of glycemic control, especially diabetes and impaired glucose metabolism. This invention provides methods to classify patients for treatment and/or for optimization of clinical studies and to treat patients based on this association.

Claims

1. A method for determining the responsiveness of an individual with a disorder characterized by impaired glycemic control to treatment with a glycemic control agent or therapy, comprising;

(a) determining for the two copies of the TCF1 gene present in the individual, the identity of the nucleotide pair at the polymorphic site at 483 A>

G, and

(b) assigning the individual to a good responder group if both pairs are GC or if one pair is AT and one pair is GC and to a low responder group if both pairs are AT.

2. The method of claim 1 wherein the glycemic control agent or therapy comprises administration of a dipeptidylpeptidase 4 (DPP4) inhibitor.

3. The method of claim 1 wherein the glycemic control agent or therapy comprises administration of 2-Pyrrolidinecarbonitrile, 1-[[[2-[(5-cyano-2-pyridinyl) amino]ethyl]amino]acetyl]-, (2S).

4. The method of claim 1 wherein the glycemic control agent or therapy comprises administration of 1-[3Hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile.

5. The method of claim 1 wherein the glycemic control agent or therapy is selected from the compounds of Formula I or Formula II.

6. The method of claim 1 wherein the disorder characterized by impaired glycemic control is type 2 diabetes mellitus.

7. The method of claim 1 wherein the disorder characterized by impaired glycemic control is type 1 diabetes mellitus.

8. The method of claim 1 wherein the disorder characterized by impaired glycemic control is impaired glucose tolerance.

9. The method of claim 1 wherein the disorder characterized by impaired glycemic control is impaired fasting glucose.

10. The method of claim 1 wherein the disorder characterized by impaired glycemic control is Syndrome X.

11. The method of claim 1 wherein the disorder characterized by impaired glycemic control is gestational diabetes.

12. The method of claim 1 wherein the disorder characterized by impaired glycemic control is impaired glucose metabolism (IGM).

13. The method of claim 1 wherein the disorder characterized by impaired glycemic control is a disorder responsive to DPP4 inhibitors

54. A method according to claim 1, wherein the determination step (a) further comprises the use a kit according to claim 47.

55. A method according to claim 1, wherein said method is performed ex vivo.

14. A method for treating an individual with a disorder characterized by impaired glycemic control, comprising,

(a) determining, for the two copies of the TCF1 gene present in the individual, the identity of the nucleotide pair at the polymorphic site 483 A>

G, wherein,

(b) if both the nucleotide pairs are CG or if one is AT and one is CG the individual is treated with a glycemic control agent or therapy and if the nucleotide pairs are both AT the individual is treated with alternate therapy.

15. The method of claim 14 wherein the glycemic control agent or therapy comprises administration of a dipeptidylpeptidase 4 (DPP4) inhibitor.

16. The method of claim 14 wherein the glycemic control agent or therapy comprises administration of 2-Pyrrolidinecarbonitrile, 1-[[[2-[(5-cyano-2-pyridinyl) amino]ethyl]amino]acetyl]-, (2S).

17. The method of claim 14 wherein the glycemic control agent or therapy comprises administration of 1-[3Hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile.

18. The method of claim 14 wherein the glycemic control agent is selected from the compounds of Formula I or Formula II.

19. The method of claim 14 wherein the disorder characterized by impaired glycemic control is type 2 diabetes mellitus.

20. The method of claim 14 wherein the disorder characterized by impaired glycemic control is type 1 diabetes mellitus.

21. The method of claim 14 wherein the disorder characterized by impaired glycemic control is impaired glucose tolerance.

22. The method of claim 14 wherein the disorder characterized by impaired glycemic control is impaired fasting glucose.

23. The method of claim 14 wherein the disorder characterized by impaired glycemic control is Syndrome X.

24. The method of claim 14 wherein the disorder characterized by impaired glycemic control is gestational diabetes.

25. The method of claim 14 wherein the disorder characterized by impaired glycemic control is impaired glucose metabolism (IGM).

26. The method of claim 14 wherein the disorder characterized by impaired glycemic control is a disorder responsive to DPP4 inhibitors.

28. The method of claim 26, wherein the trait is a clinical response to a drug targeting TCF1 or DPP4.

27. A method for identifying an association between a trait and at least one genotype or haplotype of the TCF1 gene which comprises, comparing the frequency of the genotype or haplotype in a population exhibiting the trait with the frequency of the genotype or haplotype in a reference population, wherein the genotype or haplotype comprises a nucleotide pair or nucleotide located at the polymorphic site 483 A>

G, wherein a higher frequency of the genotype or haplotype in the trait population than in the reference population indicates the trait is associated with the genotype or haplotype.

29. A method for treating an individual, with a disorder characterized by impaired glycemic control, comprising,

(a) determining, for the two copies of the TCF1 gene present in the individual, the identity of the nucleotide pair at the polymorphic site 483 A>

G, wherein,

(b) if both the nucleotide pairs are CG or if one is AT and one is CG the individual is treated with a low dose of a glycemic control agent and if the nucleotide pairs are both AT the individual is treated with a high dose of a glycemic control agent.

30. The method of claim 29 wherein the glycemic control agent is a dipeptidylpeptidase 4 (DPP4) inhibitor.

31. The method of claim 29 wherein the glycemic control agent or therapy comprises administration of 2-Pyrrolidinecarbonitrile, 1-[[[2-[(5-cyano-2-pyridinyl) amino]ethyl]amino]acetyl]-, (2S).

32. The method of claim 29 wherein the glycemic control agent or therapy comprises administration of 1-[3Hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile.

33. The method of claim 29 wherein the glycemic control agent or therapy is selected from the compounds of Formula I or Formula II.

34. The method of claim 29 wherein the disorder characterized by impaired glycemic control is type 2 diabetes mellitus.

35. The method of claim 29 wherein the disorder characterized by impaired glycemic control is type 1 diabetes mellitus.

36. The method of claim 29 wherein the disorder characterized by impaired glycemic control is impaired glucose tolerance.

37. The method of claim 29 wherein the disorder characterized by impaired glycemic control is impaired fasting glucose.

38. The method of claim 29 wherein the disorder characterized by impaired glycemic control is Syndrome X.

39. The method of claim 29 wherein the disorder characterized by impaired glycemic control is gestational diabetes.

40. The method of claim 29 wherein the disorder characterized by impaired glycemic control is impaired glucose metabolism (IGM).

41. The method of claim 29 wherein the disorder characterized by impaired glycemic control is a disorder responsive to DPP4 inhibitors.

42. A method of treating a patient with a disorder characterized by impaired glycemic control comprising,

(a) providing genetic counseling to the patient and patients family,

(b) determining the patients genotype for the TCF1 gene at the polymorphism site 483 A>

G,

(c) determining the proper therapy for said patient based on results of the genotype determination.

43. A method for optimizing clinical trial design for glycemic control agents, comprising,

(a) determining, for the two copies of the TCF1 gene present in an individual being considered for inclusion in the clinical trial, the identity of the nucleotide pair at the polymorphic site 483 A>

G wherein,

(b) if both the nucleotide pairs are CG or if one is AT and one is CG the individual is included in the clinical trial and if the nucleotide pairs are both AT the individual is not included.

44. A method for identifying individuals, with a disorder characterized by impaired glycemic control, who would benefit from drug A vs. B, comprising,

(a) determining, for the two copies of the TCF1 gene present in the individual, the identity of the nucleotide pair at the polymorphic site 483 A>

G, wherein,

(b) both the nucleotide pairs are CG or if one is AT and one is CG the individual would benefit from a glycemic control agent or therapy and if the nucleotide pairs are both AT the individual would benefit from alternate glycemic control therapy.

45. A method for determining which individuals, with a disorder characterized by impaired glycemic control, could be treated with a glycemic control agents with reduced side effects, comprising, determining, for the two copies of the TCF1 gene present in the individual, the identity of the nucleotide pair at the polymorphic site 483 A>

G, wherein, if both the nucleotide pairs are CG or if one is AT and one is CG the individual can be treated with lower doses of a glycemic control agent with fewer side effects and if the nucleotide pairs are both AT the individual must be treated with higher doses of a glycemic control agent and therefore greater side effects.

46. A method for determining the responsiveness of an individual with a disorder characterized by impaired glycemic control to treatment with a glycemic control agent or therapy, comprising;

(a) determining, for the two copies of the TCF1 gene present in the individual, the identity of a nucleotide pair at a polymorphic site in the region of the TCF1 gene that is in linkage disequilibrium with the polymorphic site at TCF1 483 A>

G, and

(b) assigning the individual to a good responder group if the nucleotide pair at a polymorphic site in the region of the TCF1 gene that is in linkage disequilibrium with the polymorphic site at 483 A>

G indicates that, at the TCF1 polymorphic site at 483 A>

G, both nucleotide pairs are GO or one pair is AT and one pair is GC and to a low responder group if said nucleotide pair indicates that both pairs are AT at the TCF1 483 A>

G site.

47. A kit for the identification of a patient'"'"'s polymorphism pattern at the TCF1 polymorphic site at 483 A>

G, said kit comprising a means for determining a genetic polymorphism pattern at the TCF1 polymorphic site at 483 A>

G.

48. A kit according to claim 47, further comprising a DNA sample collecting means.

49. A kit according to claim 47, wherein the means for determining a genetic polymorphism pattern at the TCF1 polymorphic site at 483 A>

G comprise at least one TCF1 genotyping oligonucleotide.

50. A kit according to claim 47 wherein the means for determining a genetic polymorphism pattern at the TCF1 polymorphic site at 483 A>

G comprise two TCF1 genotyping oligonucleotides.

51. A kit according to claim 47, wherein the means for determining a genetic polymorphism pattern at the TCF1 polymorphic site at 483 A>

G comprise at least one TCF1 genotyping primer compositor comprising at least one TCF1 genotyping oligonucleotide.

52. A kit according to claim 51, wherein the TCF1 genotyping primer compositor comprises at least two sets of allele specific primer pairs.

53. A kit according to claim 50, wherein the two TCF1 genotyping oligonucleotides are packaged in separate containers.