Methods and compositions for preserving retinal ganglion cells

• US 10,617,735 B2
• Filed: 04/18/2018
• Issued: 04/14/2020
• Est. Priority Date: 11/01/2010
• Status: Active Grant

• 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 G., Miller, Joan W., Kayama, Maki
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): Lockard, Jon M
• Application Number:
  US15/956,133
• Publication Number:
  US 20190099467A1
• Time in Patent Office: 727 Days
• Field of Search: None
• 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 selected from the group consisting of an optic neuropathy and diabetic retinopathy, 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 selected from the group consisting of necrostatin-1, necrostatin-2, necrostatin-3, necrostatin-4, necrostatin-5, necrostatin-7, and related compounds, and an effective amount of an apoptosis inhibitor selected from the group consisting of a pan-caspase inhibitor, a caspase-1 inhibitor, a caspase-3 inhibitor, a caspase-8 inhibitor, and a caspase-9 inhibitor, thereby to preserve the viability of a retinal ganglion cell 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 2, wherein the visual function is visual acuity.

4. The method of claim 1, wherein the ocular condition is an optic neuropathy selected from the group consisting of an ischemic optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, a mitochondrial optic neuropathy, nutritional optic neuropathy, toxic optic neuropathy, and a hereditary optic neuropathy.

5. The method of claim 4, wherein the ischemic optic neuropathy is selected from the group consisting of arteritic anterior ischemic neuropathy, non-arteritic anterior ischemic neuropathy, and posterior ischemic optic neuropathy.

6. The method of claim 4, wherein the mitochondrial optic neuropathy is Leber'"'"'s optic neuropathy.

7. The method of claim 4, wherein the hereditary optic neuropathy is selected from the group consisting of Leber'"'"'s optic neuropathy, Dominant Optic Atrophy, and Behr'"'"'s syndrome.

8. The method of claim 1, wherein the ocular condition is diabetic retinopathy.

9. The method of claim 1, wherein the necrosis inhibitor is necrostatin-1.

10. The method of claim 1, wherein the necrosis inhibitor is administered to provide a final concentration of the necrosis inhibitor in the eye greater than about 10 μ

M.

11. The method of claim 1, wherein from about 0.05 mg to about 2 mg of the necrosis inhibitor is administered.

12. The method of claim 1, wherein the pan-caspase inhibitor is zVAD, IDN-6556, or a combination thereof.

13. The method of claim 1, wherein from about 0.15 mg to about 1.5 mg of the pan-caspase inhibitor is administered.

14. The method of claim 1, wherein the necrosis inhibitor, the apoptosis inhibitor, or both the necrosis inhibitor and the apoptosis inhibitor are administered to the eye.

15. The method of claim 1, wherein the necrosis inhibitor, the apoptosis inhibitor, or both the necrosis inhibitor and the apoptosis inhibitor are administered by intraocular injection.

16. The method of claim 15, wherein the necrosis inhibitor, the apoptosis inhibitor, or both the necrosis inhibitor and the apoptosis inhibitor are administered intravitreally.

17. The method of claim 1, wherein the necrosis inhibitor, the apoptosis inhibitor, or both the necrosis inhibitor and the apoptosis inhibitor are administered sequentially or simultaneously.

18. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula I:

19. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula I-A:

20. The method of claim 1, wherein the necrosis inhibitor is a compound selected from the group consisting of a compound of Formula I-B:

21. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula I-E:

22. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula II:

23. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula II-A:

24. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula III:

25. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula IV:

26. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula V:

27. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula V-A:

28. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula VII:

29. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula VIII:

30. The method of claim 1, wherein the necrosis inhibitor is a compound of Formula IX: