Treating cognitive decline and other neurodegenerative conditions by selectively removing senescent cells from neurological tissue

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 of selectively eliminating senescent cells in tissues of a brain, comprising contacting senescent cells in tissues of the brain with a senolytic agent that is an MDM2 inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the MDM2 senolytic agent is a small molecule inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the MDM2 senolytic agent is a polynucleotide or oligonucleotide. 
     
     
         4 . The method of  claim 3 , wherein the MDM2 senolytic agent that is a polynucleotide or oligonucleotide is an antisense oligonucleotide, siRNA or shRNA. 
     
     
         5 . The method of  claim 1 , wherein the MDM2 senolytic agent is administered to the senescent cells in tissues of the brain intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         6 . The method of  claim 5 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         7 . The method of  claim 2 , wherein the MDM2 senolytic small molecule inhibitor is administered to the senescent cells in tissues of the brain intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         8 . The method of  claim 7 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         9 . The method of  claim 4 , wherein the MDM2 senolytic antisense oligonucleotide is administered to the senescent cells in tissues of the brain intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         10 . The method of  claim 9 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         11 . A method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a MDM2 senolytic agent. 
     
     
         12 . The method of  claim 11 , wherein the MDM2 senolytic agent is a small molecule inhibitor. 
     
     
         13 . The method of  claim 11 , wherein the MDM2 senolytic agent is a polynucleotide or oligonucleotide. 
     
     
         14 . The method of  claim 13 , wherein the MDM2 senolytic agent is an antisense oligonucleotide, siRNA or shRNA. 
     
     
         15 . The method of  claim 11 , wherein the MDM2 senolytic agent is administered to the subject in need thereof intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         16 . The method of  claim 15 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         17 . The method of  claim 12 , wherein the MDM2 senolytic small molecule inhibitor is administered to the subject in need thereof intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         18 . The method of  claim 17 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         19 . The method of  claim 14 , wherein the MDM2 senolytic antisense oligonucleotide is administered to the subject in need thereof intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval. 
     
     
         20 . The method of  claim 19 , wherein the non-treatment interval is between at least about 0.5 to 12 months. 
     
     
         21 . The method of  claim 16 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction. 
     
     
         22 . The method of  claim 18 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction. 
     
     
         23 . The method of  claim 20 , wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction. 
     
     
         24 . The method of  claim 12 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration. 
     
     
         25 . The method of  claim 13 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration. 
     
     
         26 . The method of  claim 14 , wherein the administration of the pharmaceutical composition to the subject is by intracranial administration or intranasal administration.