Therapy for removing senescent cells and treating senescence-associated disease using an mdm2 inhibitor

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.

1 . A method for treating a disease or disorder that is not a cancer in a target tissue in a subject,
 the method comprising administering to the subject a pharmaceutical composition that contains a formulation of an effective amount of a senolytic agent that is less than 10,000 mol. wt., the senolytic agent being a means for inhibiting mouse double minute 2 homolog (MDM2),   wherein the administering of the composition to the subject is effective in selectively removing at least some p16-positive senescent cells from the target tissue.   
     
     
         2 . The method of  claim 1 , wherein the means for inhibiting MDM2 is a cis-imidazoline, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the means for inhibiting MDM2 is selected from Nutlin-1, Nutlin-2, RG-7112, RG7388, DS-3032b, MI-63, MI-126, MI-122, MI-142, MI-147, MI-219, MI-220, MI-221, MI-773, 3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropypmethoxy)-2-(4-nitrobenzyl)isoindolin-1-one, Serdemetan, AM-8553, CGM097, RO-2443, RO-5963, 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid, 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid, TDP521252, TDP665759, NSC279287, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The method of  claim 1 , wherein the means for inhibiting MDM2 is 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone or a pharmaceutically acceptable salt thereof (Nutlin-3a), or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical composition is administered in a course of therapy that includes a treatment period during which the pharmaceutical composition is administered to the subject in one or a plurality of doses, followed by a therapeutic period of at least two weeks during which the pharmaceutical composition is not administered but one or more symptoms of the disease or disorder in the target tissue are alleviated. 
     
     
         6 . The method of  claim 5 , wherein a single dose of the pharmaceutical composition is administered to the subject during the treatment period, and the therapeutic period lasts at least one month. 
     
     
         7 . The method of  claim 1 , wherein the disease or disorder is osteoarthritis. 
     
     
         8 . The method of  claim 7 , wherein the pharmaceutical composition is administered in or around an osteoarthritic joint of the subject. 
     
     
         9 . The method of  claim 8 , whereby erosion of a proteoglycan layer is inhibited and/or production of collagen Type II is induced in an osteoarthritic joint of the subject. 
     
     
         10 . The method of  claim 8 , whereby pain being experienced by the subject in an osteoarthritic joint is relieved. 
     
     
         11 . The method of  claim 1 , wherein the disease or disorder is a neurodegenerative disease or an ophthalmic disease. 
     
     
         12 . The method of  claim 1 , wherein the disease or disorder is a lung disease. 
     
     
         13 . The method of  claim 12 , wherein the lung disease is idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or a pulmonary disease that has been caused or exacerbated by smoking. 
     
     
         14 . The method of  claim 12 , wherein the composition is administered by inhalation. 
     
     
         15 . The method of  claim 1 , wherein the disease or disorder is atherosclerosis. 
     
     
         16 . The method of  claim 15 , wherein the composition is administered systemically. 
     
     
         17 . The method of  claim 1 , further comprising monitoring senescent cells in or around the target tissue of the subject following the administering of the composition. 
     
     
         18 . A method for treating a disease or disorder that is not a cancer in a target tissue in a subject,
 the method comprising administering to the subject a pharmaceutical composition that contains a formulation of an effective amount of a compound that is a cis-imidazoline,   wherein the administering of the composition to the subject is effective in selectively removing at least some p16-positive senescent cells from the target tissue.   
     
     
         19 . The method of  claim 18 , wherein the cis-imidazoline is selected from Nutlin-1, Nutlin-2, Nutlin-3a, RG-7112, and pharmaceutically acceptable salts thereof. 
     
     
         20 . The method of  claim 18 , wherein the pharmaceutical composition is administered in or around an osteoarthritic joint of the subject.