Methods and compositions for preserving photoreceptor and retinal pigment epithelial cells

• US 10,149,884 B2
• Filed: 10/07/2016
• Issued: 12/11/2018
• 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
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): Lockard, Jon M
• Application Number:
  US15/288,214
• Publication Number:
  US 20170216393A1
• Time in Patent Office: 795 Days
• Field of Search: None
• 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

(i) an ocular condition selected from central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, and pattern dystrophy;

(ii) an ocular condition selected from Cone-Rod dystrophy, North Carolina dystrophy, Usher'"'"'s Syndrome, Bardet-Biedl Syndrome, and intraocular inflammation;

(iii) an ocular condition selected from Stargardt'"'"'s Disease, inflammatory retinopathy, infectious retinopathy, myopic degeneration, diabetic retinopathy, macular edema, and central serous retinopathy;

or

(iv) an ocular condition selected from uveitis, multiple evanescent white dot syndrome, serpiginous choroidopathy, and acute multifocal posterior placoid epitheliopathy (AMPPE),

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

4. 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.

5. 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.

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

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

8. The method of claim 7, wherein the pan-caspase inhibitor is zVAD, IDN-6556 or a combination thereof.

9. The method of claim 7, wherein the pan-caspase inhibitor is administered to provide a final concentration in the eye greater than about 100 μ

M.

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

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