METHODS AND COMPOSITIONS FOR PRESERVING PHOTORECEPTOR AND RETINAL PIGMENT EPITHELIAL CELLS

• US 20160250189A1
• Filed: 11/06/2015
• Published: 09/01/2016
• Est. Priority Date: 04/23/2010
• 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, Trichonas, Georgios, Miller, Joan W., Murakami, Yusuke
• Granted Patent: US 9,492,432 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61B 3/028 for testing visual acuity; for determination of refraction, e.g. phoropters
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61F 9/0008 Introducing ophthalmic products into the ocular cavity or retaining products therein putting in contact lenses A61F9/0061; introducing or retaining media in cavities of the body in general A61M31/00
• 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 31/12 Ketones
• 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 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Provided are methods and compositions for maintaining the viability of photoreceptor cells and/or retinal pigment epithelial cells in a subject with an ocular disorder including, for example, age-related macular degeneration (AMD) (e.g., dry or neovascular AMD), retinitis pigmentosa (RP), or a retinal detachment. The viability of the photoreceptor cells and/or the retinal pigment epithelial 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, 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 retinal detachment, age-related macular degeneration and retinitis pigmentosa, wherein a symptom of the ocular condition is the loss of photoreceptor 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 necrostatin 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 photoreceptor cells disposed within the retina of the eye; and

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

wherein the necrostatin is selected from the group consisting of;

(i) a Nec-1 related compound of Formula I;

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

3-8. -8. (canceled)

9. A method of preserving the viability of photoreceptor cells disposed within a retina of a mammalian eye following retinal detachment, the method comprising:

administering a necrostatin and 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 to the eye in which a region of the retina has been detached in amounts sufficient to preserve the viability of photoreceptor cells disposed within the region of the detached retina, provided that, when necrostatin-1 is the only necrostatin administered, the region is exposed to a final concentration of necrostatin-1 in the eye greater than about 100 μ

M;

wherein the necrostatin is selected from the group consisting of;

(i) a Nec-1 related compound of Formula I;

10. The method of claim 9, wherein the retinal detachment is a rhegmatogenous retinal detachment, a tractional retinal detachment, or a serous retinal detachment.

11. A method of preserving visual function of an eye of a subject with an ocular condition selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa, macular edema, central areolar choroidal dystrophy, retinal detachment, diabetic retinopathy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt'"'"'s disease, Cone-Rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, toxic retinitis and light-induced toxicity, wherein a symptom of the ocular condition is the loss of photoreceptor 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 photoreceptor cells disposed with the retina of the eye.

12. (canceled)

13. The method of claim 11, 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.

14. The method of claim 13, wherein the RIP kinase inhibitor is a necrostatin.

15. (canceled)

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

17-18. -18. (canceled)

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

20. (canceled)

21. The method of claim 1, wherein the necrostatin is administered to provide a final concentration of necrostatin in the eye greater than about 100 μ

M.

22-24. -24. (canceled)

25. The method of claim 1, wherein from about 0.05 mg to about 2 mg of necrostatin is administered.

26-27. -27. (canceled)

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

29. The method of claim 28, wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof.

30. The method of claim 28, wherein the pan-caspase inhibitor is administered to provide a final concentration in the eye greater than about 100 μ

M.

31-35. -35. (canceled)

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

37-39. -39. (canceled)

40. The method of claim 1, wherein the necrostatin, the apoptosis inhibitor, or both the necrostatin and the apoptosis inhibitor are administered systemically.

41. (canceled)

42. The method of claim 1, wherein, when the ocular condition is a retinal detachment, the necrostatin and/or the apoptosis inhibitor is administered to the subject prior to reattachment of the retina or a region of the retina that has detached.

43. The method of claim 1, when the ocular condition is a retinal detachment, the necrostatin and/or the apoptosis inhibitor is administered to the subject after reattachment of the retina or a region of the retina that has detached.

44-61. -61. (canceled)