Methods to screen and treat individuals with glaucoma or the propensity to develop glaucoma

• US 20030119000A1
• Filed: 11/05/2001
• Published: 06/26/2003
• Est. Priority Date: 11/05/2001
• Status: Abandoned Application

• Current Assignee: Insite Vision Incorporated (Daiichi Sankyo Company Limited)
• Original Assignee: Insite Vision Incorporated (Daiichi Sankyo Company Limited)
• Inventors: Polansky, Jon
• Application Number:
  US09/985,637
• Publication Number:
  US 20030119000A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• 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

The present invention involves methods and reagents for diagnosing and treating glaucoma and related disorders. Specifically, the invention relates to a method of identifying mutations in the TIGR gene of a glaucomatous patient and treating them with an effective amount of a non-steroidal anti-inflammatory drug. Additionally the invention allows the identification of individuals at risk for progressive increases in intraocular pressure, which is a risk factor for glaucoma; the invention thus also allows the identification of individuals among ocular hypertensive/glaucoma suspect groups at increased risk of visual field loss.

Claims

1. A method of providing treatment to a glaucomatous patient comprising:

(a) determining whether said patient has a mutation in the TIGR promoter selected from the group consisting of TIGRmt1, TIGRmt11, or both TIGRmt1 and TIGRmt11; and

(b) administering an effective amount of a non-steroidal anti-inflammatory drug to said patient.

2. The method of claim 1, wherein said glaucoma is an inherited glaucoma.

3. The method of claim 2, wherein said glaucoma is an open angle glaucoma.

4. The method of claim 3, wherein said open angle glaucoma is primary open angle glaucoma.

5. The method of claim 1, where said mutation is determined through the use of nucleic acid amplification methods.

6. The method of claim 1, where said mutation is determined through the use of a marker nucleic acid molecule.

7. The method of claim 1, wherein said mutation is determined using a restriction endonuclease.

8. The method of claim 1, where said mutation is determined using oligonucleotide probes.

9. The method of claim 1, wherein said non-steroidal anti-inflamatory drug is administered using a polymeric carrier.

10. The method of claim 9, wherein said polymeric carrier is a lightly crosslinked polymer of acrylic acid.

11. The method of claim 10, wherein said lightly crosslinked polymer is prepared in an aqueous suspension.

12. The method of claim 1, wherein said non-steroidal anti-inflammatory drug is administered in a topical formulation.

13. The method of claim 1, wherein said non-steroidal anti-inflammatory drug is administered in an ocular injection.

14. The method of claim 1, wherein said non-steroidal anti-inflammatory drug is administered orally.

15. The method of claim 1, wherein said non-steroidal anti-inflammatory drug is a cyclooxygenase inhibiting agent.

16. The method of claim 15, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of salicylates, fenamates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolons.

17. The method of claim 15, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of aspirin, salicylic acid, diflunisol, indomethacin, sulinda, tolmetin, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, naproxen, piroxicam, suprofen, diclofenac, oxyphenbutazone, phenylbutazone, antipyrine, aminopyrne, and azapropazone.

18. The method of claim 16, wherein said cyclooxygenase inhibiting agent is a phenylacetic acid.

19. The method of claim 18, wherein said phenylacetic acid is diclofenac.

20. The method of claim 1, wherein said effective amount is greater than about 0.01% by weight of a non-steroidal anti-inflammatory drug.

21. The method of claim 20, wherein said effective amount is greater than about 0.03% by weight of a non-steroidal anti-inflammatory drug.

22. The method of claim 21, wherein said effective amount is greater than about 0.06% by weight of a non-steroidal anti-inflammatory drug.

23. The method of claim 22, wherein said effective amount is greater than about 0.1% by weight of a non-steroidal anti-inflammatory drug.

24. A method of preventing increases in intraocular pressure in a patient predisposed to developing glaucoma comprising:

(a) determining whether said patient has a mutation in the TIGR gene selected from the group consisting of TIGRmt1, TIGRmt11, or both TIGRmt1 and TIGRmt11; and

(b) administering an effective amount of a non-steroidal anti-inflammatory drug to said patient.

25. The method of claim 24, wherein said patient is asymptomatic of glaucoma.

26. The method of claim 24, wherein said intraocular pressure is below about 25 mm Hg.

27. The method of claim 26, wherein said intraocular pressure is below about 22 mm Hg.

28. The method of claim 27, wherein said intraocular pressure is below about 20 mm Hg.

29. The method of claim 24, wherein said glaucoma is an inherited glaucoma.

30. The method of claim 29, wherein said glaucoma is an open angle glaucoma.

31. The method of claim 30, wherein said open angle glaucoma is primary open angle glaucoma.

32. The method of claim 24, where said mutation is determined through the use of nucleic acid amplification methods.

33. The method of claim 24, where said mutation is determined through the use of a marker nucleic acid molecule.

34. The method of claim 24, wherein said mutation is determined using a restriction endonuclease.

35. The method of claim 24, where said mutation is determined using oligonucleotide probes.

36. The method of claim 24, wherein said non-steroidal anti-inflamatory drug is administered using a polymeric carrier.

37. The method of claim 36, wherein said polymeric carrier is a lightly crosslinked polymer of acrylic acid.

38. The method of claim 37, wherein said lightly crosslinked polymer is prepared in an aqueous suspension.

39. The method of claim 24, wherein said non-steroidal anti-inflammatory drug is administered in a topical formulation.

40. The method of claim 24, wherein said non-steroidal anti-inflammatory drug is administered in an ocular injection.

41. The method of claim 24, wherein said non-steroidal anti-inflammatory drug is administered orally.

42. The method of claim 24, wherein said non-steroidal anti-inflammatory drug is a cyclooxygenase inhibiting agent.

43. The method of claim 42, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of salicylates, fenamates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolons.

44. The method of claim 42, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of aspirin, salicylic acid, diflunisol, indomethacin, sulinda, tolmetin, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, naproxen, piroxicam, suprofen, diclofenac, oxyphenbutazone, phenylbutazone, antipyrine, aminopyrine, and azapropazone.

45. The method of claim 43, wherein said cyclooxygenase inhibiting agent is a phenylacetic acid.

46. The method of claim 45, wherein said phenylacetic acid is diclofenac.

47. The method of claim 24, wherein said effective amount is greater than about 0.01% by weight of a non-steroidal anti-inflammatory drug.

48. The method of claim 47, wherein said effective amount is greater than about 0.03% by weight of a non-steroidal anti-inflammatory drug.

49. The method of claim 48, wherein said effective amount is greater than about 0.06% by weight of a non-steroidal anti-inflammatory drug.

50. The method of claim 49, wherein said effective amount is greater than about 0.1% by weight of a non-steroidal anti-inflammatory drug.

60. The method of claim 49, wherein said effective amount is greater than about 0.01% of a non-steroidal anti-inflammatory drug by weight.

61. The method of claim 60, wherein said effective amount is greater than about 0.03% of a non-steroidal anti-inflammatory drug by weight.

62. The method of claim 61, wherein said effective amount is greater than about 0.06% of a non-steroidal anti-inflammatory drug by weight.

63. The method of claim 62, wherein said effective amount is greater than about 0.1% of a non-steroidal anti-inflammatory drug by weight.

64. The method of claim 49, wherein said glaucoma is an inherited glaucoma.

65. The method of claim 64, wherein said glaucoma is an open angle glaucoma.

67. The method of claim 49, where said mutation is determined through the use of nucleic acid amplification methods.

68. The method of claim 49, where said mutation is determined through the use of a marker nucleic acid molecule.

69. The method of claim 49, wherein said mutation is determined u sing a restriction endonuclease.

70. The method of claim 49, where said mutation is determined using oligonucleotide probes.

71. The method of claim 49, wherein said non-steroidal anti-inflamatory drug is administered using a polymeric carrier.

72. The method of claim 71, wherein said polymeric carrier is a lightly crosslinked polymer of acrylic acid.

73. The method of claim 72, wherein said lightly crosslinked polymer is prepared in an aqueous suspension.

74. The method of claim 49, wherein said non-steroidal anti-inflammatory drug is administered in a topical formulation.

75. The method of claim 49, wherein said non-steroidal anti-inflammatory drug is administered in an ocular injection.

76. The method of claim 49, wherein said non-steroidal anti-inflammatory drug is administered orally.

51. A method for decreasing the mean diurnal intra-ocular pressure in a patient, comprising

(a) identifying the presence of at least one mutation in the TIGR gene selected from the group consisting of TIGRmt1, TIGRmt11, or both TIGRmt1 and TIGRmt11;

and

(b) administering an effective amount of a non-steroidal anti-inflammatory drug to said patient.

52. The method of claim 51, wherein said non-steroidal anti-inflammatory drug is cyclooxygenase inhibiting agent.

53. The method of claim 52, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of salicylates, fenamates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolons.

54. The method of claim 52, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of aspirin, salicylic acid, diflunisol, indomethacin, sulinda, tolmetin, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, naproxen, piroxicam, suprofen, diclofenac, oxyphenbutazone, phenylbutazone, antipyrine, aminopyrine, and azapropazone.

55. The method of claim 53, wherein said cyclooxygenase inhibiting agent is a phenylacetic acid.

56. The method of claim 55, wherein said phenylacetic acid is diclofenac.

57. The method of claim 51, wherein said decrease in mean diurnal intra-ocular pressure is greater than about 1 mm Hg per 6 months.

58. The method of claim 57, wherein said decrease in mean diurnal intra-ocular pressure is greater than about 2.5 mm Hg per 6 months.

59. The method of claim 58, wherein said decrease in mean diurnal intra-ocular pressure is greater than about 3 mm Hg per 6 months.

77. A method of providing treatment to a patient known to possess at least one mutation in the TIGR gene selected from the group consisting of TIGRmt1 and TIGRmt11 comprising:

(a) administering an effective amount of a non-steroidal anti-inflammatory drug to said patient; and

(b) monitoring the level of intraocular pressure of said patient.

66. The method of claim 92, wherein said open angle glaucoma is primary open angle glaucoma.

78. The method of claim 77, wherein said non-steroidal anti-inflammatory drug is a cyclooxygenase inhibiting agent.

79. The method of claim 78, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of salicylates, fenamates, indoles, phenylalkanoic acids, phenylacetic acids, and pyrazolons.

80. The method of claim 78, wherein said cyclooxygenase inhibiting agent is selected from the group consisting of aspirin, salicylic acid, diflunisol, indomethacin, sulinda, tolmetin, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, naproxen, piroxicam, suprofen, diclofenac, oxyphenbutazone, phenylbutazone, antipyrine, aminopyrine, and azapropazone.

81. The method of claim 79, wherein said cyclooxygenase inhibiting agent is a phenylacetic acid.

82. The method of claim 81, wherein said phenylacetic acid is diclofenac.

83. The method of claim 77, wherein said effective amount is greater than about 0.01% of a non-steroidal anti-inflammatory drug by weight.

84. The method of claim 83, wherein said effective amount is greater than about 0.03% of a non-steroidal anti-inflammatory drug by weight.

85. The method of claim 84, wherein said effective amount is greater than about 0.06% of a non-steroidal anti-inflammatory drug by weight.

86. The method of claim 85, wherein said effective amount is greater than about 0.1% of a non-steroidal anti-inflammatory drug by weight.

87. The method of claim 77, wherein said level of intraocular pressure is below about 25 mm Hg after six months.

88. The method of claim 87, wherein said level of intraocular pressure is below about 22 mm Hg after six months.

89. The method of claim 88, wherein said level of intraocular pressure is below about 20 mm Hg after six months.

90. The method of claim 77, wherein said patient is asymptomatic for glaucoma.

91. The method of claim 77, wherein said glaucoma is an inherited glaucoma.

92. The method of claim 91, wherein said glaucoma i s an open angle glaucoma.

93. The method of claim 92, wherein said open angle glaucoma is primary open angle glaucoma.

94. The method of claim 77, where said mutation is determined through the use of nucleic acid amplification methods.

95. The method of claim 77, where said mutation is determined through the use of a marker nucleic acid molecule.

96. The method of claim 77, wherein said mutation is determined using a restriction endonuclease.

97. The method of claim 77, where said mutation is determined using oligonucleotide probes.

98. The method of claim 77, wherein said non-steroidal anti-inflamatory drug is administered using a polymeric carrier.

99. The method of claim 98, wherein said polymeric carrier is a lightly crosslinked polymer of acrylic acid.

100. The method of claim 99, wherein said lightly crosslinked polymer is prepared in an aqueous suspension.

101. The method of claim 77, wherein said non-steroidal anti-inflammatory drug is administered in a topical formulation.

102. The method of claim 77, wherein said non-steroidal anti-inflammatory drug is administered in an ocular injection.

103. The method of claim 77, wherein said non-steroidal anti-inflammatory drug is administered orally.

104. A method of selecting a patient for a clinical trial involving a treatment for elevated intraocular pressure, comprising:

determining whether said patient has either the TIGRmt1 mutation, or both the TIGRmt1 and TIGRmt11 mutations; and

,

selecting said patient if said patient has said TIGRmt1 mutation or both of said TIGRmt1 and TIGRmt11 mutations.

105. The method of claim 104, wherein said treatment comprises administration of a medicament to said patient.

106. The method of claim 104, further comprising the step of not selecting said patient if said patient lacks said TIGRmt1 mutation.

107. The method of claim 104, wherein said mutation is said TIGRmt1.

114. The method of claim 104, wherein said mutation is said TIGRmt1.

108. A method of improving the results of a drug study involving a treatment for elevated intraocular pressure, comprising:

a) determining whether a candidate patient for inclusion in said study has either the TIGRmt1 mutation, or both the TIGRmt1 and TIGRmt11 mutations; and

,

b) selecting said patient for inclusion in said study if said patient has said TIGRmt1 mutation or both of said TIGRmt1 and TIGRmt11 mutations.

109. The method of claim 108, further comprising repeating steps a) and b) until a sufficient number of patients for said study have been selected.

110. The method of claim 108, further comprising the step of not selecting said patient if said patient lacks said TIGRmt1 mutation.

111. The method of claim 108, wherein said mutation is said TIGRmt1.

112. A method of determining whether a patient is at risk for developing elevated intraocular pressure, comprising:

determining whether said patient has either the TIGRmt1 mutation, or both the TIGRmt1 and TIGRmt11 mutations; and

,

determining that said patient is at risk for developing elevated intraocular pressure if said patient has said TIGRmt1 mutation or both of said TIGRmt1 and TIGRmt11 mutations.

113. The method of claim 112, further comprising administering a medicament to said patient to prevent an increase in intraocular pressure.

115. A method of testing the efficacy of a therapeutic agent at counteracting glaucoma pathogenic mechanisms, comprising:

a) determining whether a candidate patient for inclusion in a study has either the TIGRmt1 mutation, or both the TIGRmt1 and TIGRmt11 mutations;

b) selecting said patient for inclusion in said study if said patient has said TIGRmt1 mutation or both of said TIGRmt1 and TIGRmt11 mutations;

c) repeating steps a) and b) one or more times; and

,

d) testing said agent in said study.

116. The method of claim 115, wherein said agent comprises a member selected from the group consisting of prostaglandin inhibitors, selective or non-selective COX 1 or COX 2 inhibitors, antioxidants, neuroprotective agents, platelet activating factor antagonists, alpha agonists, beta blockers, beta agonists, prostaglandin agonists, hypotensive lipids, carbonic anhydrase inhibitors, cholinergic agents, and combinations of the foregoing.