Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders

Patent metadata

Field	Value
Publication number	US-2016339019-A1
Application number	US-201515114762-A
Country	US
Kind code	A1
Filing date	Jan 28, 2015
Priority date	Jan 28, 2014
Publication date	Nov 24, 2016
Grant date	—

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

1 . A method for treating a senescence-associated disease or disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a small molecule senolytic agent that selectively kills senescent cells over non-senescent cells; wherein the senescence-associated disease or disorder is not a cancer, wherein the senolytic agent is administered in at least two treatment cycles, wherein each treatment cycle independently comprises a treatment course of from 1 day to 3 months followed by a non-treatment interval of at least 2 weeks; provided that if the senolytic agent is an MDM2 inhibitor, the MDM2 inhibitor is administered as a monotherapy, and each treatment course is at least 5 days long during which the MDM2 inhibitor is administered on at least 5 days.

2 . The method of claim 1 , wherein the senolytic agent is selected from an MDM2 inhibitor; an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least BCL-xL; and an Akt specific inhibitor.

3 . The method of claim 2 , wherein the senolytic agent is an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least Bcl-xL and is selected from ABT-263, ABT-737, WEHI-539, and A-1155463.

4 . The method of claim 2 , wherein the senolytic agent is an MDM2 inhibitor and is Nutlin-3a or RG-1172.

5 . A method for treating a senescence-associated disease or disorder that is not a cancer, comprising administering to a subject in need thereof a therapeutically-effective amount of a small molecule senolytic agent that selectively kills senescent cells over non-senescent cells and which agent is cytotoxic to cancer cells, wherein the senolytic agent is administered as a monotherapy within at least one treatment cycle, which treatment cycle comprises a treatment course followed by a non-treatment interval; and wherein the total dose of the senolytic agent administered during the treatment cycle is an amount less than the amount effective for a cancer treatment, wherein the senolytic agent is (a) an inhibitor of a Bcl-2 anti-apoptotic protein family member that inhibits at least Bcl-xL; (b) an MDM2 inhibitor; or (c) an Akt specific inhibitor.

6 . The method of claim 5 wherein the senolytic agent is administered during two or more treatment cycles, and wherein the total dose of the senolytic agent administered during the two or more treatment cycles is an amount less than the amount effective for a cancer treatment.

7 . The method of claim 1 or claim 5 , wherein each treatment course is no longer than (a) one month, or (b) no longer than two months, or (c) no longer than 3 months.

8 . The method of claim 1 or claim 5 , wherein each treatment course is no longer than (a) 5 days, (b) 7 days, (c) 10 days, (d) 14 days, or (e) 21 days.

9 . The method of claim 1 or claim 5 , wherein the senolytic agent is administered every 2 nd day or every 3 rd day of each treatment course.

10 . The method of claim 5 , wherein the treatment course is one day, two days, three days, or four days.

11 . The method of claim 1 or claim 5 , wherein the senolytic agent is administered daily during each treatment course.

12 . The method of claim 1 or claim 5 , wherein the non-treatment interval is at least two weeks, at least one month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

13 . The method of claim 3 or claim 5 , wherein the treatment course is one day and the non-treatment interval is between 0.5-12 months.

14 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is a cardiovascular disease selected from atherosclerosis, angina, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, aortic aneurysm, cardiac diastolic dysfunction, hypercholesterolemia, hyperlipidemia, mitral valve prolapsed, peripheral vascular disease, cardiac stress resistance, cardiac fibrosis, brain aneurysm, and stroke.

15 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is an inflammatory or autoimmune disease or disorder selected from osteoarthritis, osteoporosis, oral mucositis, inflammatory bowel disease, kyphosis, and herniated intervertebral disc.

16 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction.

17 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is a metabolic disease selected from diabetes, diabetic ulcer, metabolic syndrome, and obesity.

18 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is a pulmonary disease selected from pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, cystic fibrosis, emphysema, bronchiectasis, and age-related loss of pulmonary function.

19 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is an eye disease or disorder selected from macular degeneration, glaucoma, cataracts, presbyopia, and vision loss.

20 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is an age-related disorder selected from renal disease, renal failure, frailty, hearing loss, muscle fatigue, skin conditions, skin wound healing, liver fibrosis, pancreatic fibrosis, oral submucosa fibrosis, and sarcopenia.

21 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is a dermatological disease or disorder is selected from eczema, psoriasis, hyperpigmentation, nevi, rashes, atopic dermatitis, urticaria, diseases and disorders related to photosensitivity or photoaging, rhytides; pruritis; dysesthesia; eczematous eruptions; eosinophilic dermatosis; reactive neutrophilic dermatosis; pemphigus; pemphigoid; immunobullous dermatosis; fibrohistocytic proliferations of skin; cutaneous lymphomas; and cutaneous lupus.

22 . The method of claim 1 or claim 5 , wherein the senescence-associated disease or disorder is atherosclerosis; osteoarthritis; pulmonary fibrosis; hypertension, or chronic obstructive pulmonary disease.

23 . The method of claim 1 or claim 5 , wherein the senolytic agent is administered directly to an organ or tissue that comprises the senolytic cells.

24 . The method of claim 1 or claim 5 , wherein the senolytic agent is combined with at least one pharmaceutically acceptable excipient to formulate a pharmaceutically acceptable composition to provide timed-release of the senolytic agent.

25 . The method of claim 1 or claim 5 , wherein the senolytic agent is administered as a bolus infusion.

26 . The method of claim 22 , wherein the senescence-associated disease or disorder is osteoarthritis and the senolytic agent is administered directly into the osteoarthritic joint.

27 . The method of claim 26 wherein the senolytic agent is administered intra-articularly to the osteoarthritic joint.

28 . The method of claim 26 wherein the senolytic agent is administered topically, transdermally, or intradermally.

Assignees

• Buck Inst For Res On Aging
• Unity Biotechnology Inc
• Mayo Foundation
• Univ Johns Hopkins

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Davalos Albert
• Demaria Marco
• David Nathaniel
• Vasserot Alain Philippe
• Baker Darren J
• Childs Bennett G
• Kirkland James L
• Tchkonia Tamar
• Van Deursen Jan M A
• Elisseeff Jennifer
• Kim Chaekyu
• Jeon Okhee

Classifications

• A61P19/02

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

• A61K45/06

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

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K31/496 Primary

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

• A61K31/404

  Indoles, e.g. pindolol · CPC title