METHODS AND COMPOSITIONS FOR PRESERVING RETINAL GANGLION CELLS

• US 20140024598A1
• Filed: 10/21/2011
• Published: 01/23/2014
• Est. Priority Date: 11/01/2010
• Status: Abandoned Application

• Current Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Original Assignee: Massachusetts Eye And Ear Infirmary (Foundation of The Massachusetts Eye and EAR Infirmary Incorporated)
• Inventors: Vavvas, Demetrios, Miller, Joan W., Kayama, Maki
• Application Number:
  US13/882,932
• Publication Number:
  US 20140024598A1
• Time in Patent Office: Days
• US Class Current: 514/17.7
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• 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 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

Provided are methods and compositions for maintaining the viability of retinal ganglion cells in a subject with an ocular disorder including, for example, glaucoma and optic nerve injury. The viability of the retinal ganglion cells can be preserved by administering a necrosis inhibitor either alone or in combination with an apoptosis inhibitor to a subject having an eye with the ocular condition. The compositions, when administered, maintain the viability of the cells and/or promote axon regeneration, thereby minimizing the loss of vision or visual function associated with the ocular disorder.

Claims

1. A method of preserving visual function of an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of the eye with the condition, the method comprising:

(a) administering to the eye of the subject an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to preserve the viability of retinal ganglion cells disposed within the retina of the eye; and

(b) after step (a), measuring visual function of the eye.

2. The method of claim 1, wherein, after administration of the necrosis inhibitor and the apoptosis inhibitor, the visual function of the eye is preserved or improved relative to the visual function prior to administration of the necrosis inhibitor and the apoptosis inhibitor.

3. The method of claim 1, wherein the ocular condition is selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion.

10. The method of claim 2, wherein the visual function is visual acuity.

11. The method of claim 10, wherein the ocular condition is a condition selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion.

16. The method of claim 3, wherein the ocular condition is glaucoma.

17. The method of claim 1, wherein the necrosis inhibitor is a necrostatin.

18. The method of claim 17, wherein the necrostatin is selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necreostatin-5, and necrostatin-7, or a combination thereof.

19. The method of claim 18, wherein the necrostatin is necrostatin-1.

20. The method of claim 17, wherein the necrostatin is administered to provide a final concentration of necrostatin in the eye greater than about 10 μ

M.

26. The method of claim 17, wherein from about 0.05 mg to about 2 mg of necrostatin is administered.

29. The method of claim 1, wherein the apoptosis inhibitor is a pan-caspase inhibitor.

30. The method of claim 29, wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof.

37. The method of claim 29, wherein from about 0.15 mg to about 1.5 mg of the pan-caspase inhibitor is administered.

40. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered to the eye.

42. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered by intraocular injection.

43. The method of claim 42, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered intravitreally.

45. The method of claim 17, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered sequentially or simultaneously.

46. The method of claim 17, wherein the necrostatin is a compound of Formula I:

47. The method of claim 17, wherein the necrostatin is a compound of Formula I-A:

—

48. The method of claim 17, wherein the necrostatin is a compound selected from the group consisting of a compound of Formula I-B:

4. (canceled)

5. A method of preserving visual function of an eye of a subject with an ocular condition selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of the eye, the method comprising:

reducing the production and/or activity of a RIP-1 kinase and/or a RIP-3 kinase in the eye thereby preserving the viability of the retinal ganglion cells disposed with the retina of the eye.

7. The method of claim 5, wherein the reduction in the production and/or activity of the RIP-1 kinase and/or the RIP-3 kinase is achieved by administering an effective amount of a RIP kinase inhibitor.

8. The method of claim 7, wherein the RIP kinase inhibitor is a necrostatin.

9. The method of claim 7, wherein, after step (a), the visual function of the eye is preserved or improved relative to the visual function of the eye prior to step (a).

6. (canceled)

12. A method for promoting axonal regeneration in an eye of a subject with an ocular condition, wherein a symptom of the ocular condition is the loss of retinal ganglion cell viability in the retina of an eye with the condition, the method comprising:

administering to the eye of the subject an effective amount of a necrosis inhibitor and an effective amount of an apoptosis inhibitor thereby to promote the regeneration of a retinal ganglion cell axon within the retina of the eye.

13. The method of claim 12, further comprising, after the administration of the necrosis inhibitor and the apoptosis inhibitor, measuring visual function of the eye.

14. The method of claim 13, wherein the visual function of the eye is preserved or improved relative to the visual function prior to administration of the necrosis inhibitor and the apoptosis inhibitor.

15. The method of claim 12, wherein the ocular condition is selected from the group consisting of glaucoma, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, and central retinal vein occlusion.

21-25. -25. (canceled)

27-28. -28. (canceled)

31-36. -36. (canceled)

38-39. -39. (canceled)

41. (canceled)

44. (canceled)

49-64. -64. (canceled)