Treatment of ophthalmic conditions by selectively removing senescent cells from the eye

Patent metadata

Field	Value
Publication number	US-10010546-B2
Application number	US-201715827539-A
Country	US
Kind code	B2
Filing date	Nov 30, 2017
Priority date	Jan 28, 2014
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

First claim

The invention claimed is:

1. A method of treating an ophthalmic disease or disorder in a subject, comprising:
administering in or around an eye of a subject in need thereof a pharmaceutical composition that contains an effective amount of a small-molecule means for selectively inhibiting Bcl-2 or Bcl-xL,
thereby killing senescent cells in the eye that are causing symptoms of the ophthalmic disease or disorder in the subject,
wherein the senescent cells are defined as non-cancerous cells that express p16,
the pharmaceutical composition is administered intraocularly or intravitreally, and
the pharmaceutical composition is administered in a therapeutically effective course of therapy that includes a period of treatment followed by a non-treatment interval of at least two weeks.

2. The method of claim 1 , wherein the ophthalmic disease or disorder is presbyopia.

3. The method of claim 1 , wherein the ophthalmic disease or disorder is macular degeneration.

4. The method of claim 1 , wherein the ophthalmic disease or disorder is the dry form of age-related macular degeneration.

5. The method of claim 1 , wherein the ophthalmic disease or disorder is the wet form of age-related macular degeneration.

6. The method of claim 1 , wherein the ophthalmic disease or disorder is glaucoma.

7. The method of claim 1 , wherein the pharmaceutical composition is a sustained-release formulation.

8. The method of claim 1 , wherein the pharmaceutical composition delays disorganization of type IV collagen in the eye.

9. The method of claim 1 , wherein the means for selectively inhibiting Bcl-2 or Bcl-xL is selected from WEHI-539, A-1155463, ABT-737, ABT-199, Obatoclax, BXI-61, BXI-72, 2,3-DCPE, ((R)-4-(4-chlorophenyl)-3-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl) piperazin-1-yl)phenyl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid (“Compound 21”), (R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitro phenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-ethyl-2-methyl-1H-pyrrole-3-carboxylic acid (“Compound 14”), (R)-5-(4-chlorophenyl)-4-(3-(4-(4-(4-(4-(dimethylamino)-1-(phenylthio) butan-2-ylamino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid (“Compound 15”), BM-957, BM-1074, and BM-1197.

10. The method of claim 1 , wherein the means for selectively inhibiting Bcl-2 or Bcl-xL is ABT-263 (Navitoclax).

11. The method of claim 1 , wherein a single dose of the pharmaceutical composition is administered during the period of treatment.

Assignees

• Buck Inst Res Aging
• Mayo Found Medical Education & Res
• Unity Biotechnology Inc

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Demaria Marco
• David Nathaniel
• Vasserot Alain Philippe
• Kirkland James L
• Tchkonia Tamar
• Zhu Yi
• Baker Darren J
• Childs Bennett G
• Van Deursen Jan M A

Classifications

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61K9/0073

  Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M) · CPC title