US2016244805A1PendingUtilityA1

Methods for screening to identify therapeutic agents for alzheimer's disease and use thereof

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Individually held — no corporate assignee on recordPriority: Nov 30, 2010Filed: Feb 22, 2016Published: Aug 25, 2016
Est. expiryNov 30, 2030(~4.4 yrs left)· nominal 20-yr term from priority
Inventors:Ralph A. NixonJu Hyun LeeDevin Wolfe
C12Q 1/37G01N 2333/96472G01N 2800/2821G01N 2500/10A61P 25/28A61K 31/00A61K 31/138G01N 2333/96466A61K 31/137
43
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Claims

Abstract

Methods for treating Alzheimer's Disease (AD) using modulators of lysosomal activity are described herein. More particularly, methods described herein relate to the use and application of compounds or agents that enhance lysosomal activity for the treatment of AD. In a particular aspect, the method relates to the use and application of compounds or agents that increase the pH of the lysosome and/or increase the overall activity of lysosomal proteases for the treatment of AD. Also described herein are methods and assays for screening to identify compounds or agents that increase the pH of the lysosome and/or increase the overall activity of lysosomal proteases for the treatment of AD.

Claims

exact text as granted — not AI-modified
1 . A method for treating a subject with Alzheimer's Disease (AD), wherein the subject has impaired lysosomal activity, the method comprising administering to the subject an agent that enhances lysosomal activity. 
     
     
         2 . The method of  claim 1 , wherein the impaired lysosomal activity is determined by measuring elevated pH levels in lysosomes of the subject. 
     
     
         3 . The method of  claim 2 , wherein the elevated pH level in lysosomes is equal to or greater than about 5.2. 
     
     
         4 . The method of  claim 2 , wherein the impaired lysosomal activity is determined before, concurrently, or after the administering of the agent to the subject. 
     
     
         5 . The method of  claim 2 , wherein the impaired lysosomal activity is determined before and/or after the administering of the agent to the subject. 
     
     
         6 . The method of  claim 1 , wherein the impaired lysosomal activity is determined by detecting reduced levels of lysosomal protease activity in cells of the subject. 
     
     
         7 . The method of  claim 6 , wherein the reduced levels of lysosomal protease activity in cells of the subject is reflected in reduced activity of at least three lysosomal proteases. 
     
     
         8 . The method of  claim 1 , wherein the impaired lysosomal activity is determined using a sample isolated from the subject before and/or after the administering of the agent to the subject. 
     
     
         9 . The method of  claim 8 , wherein the sample is cerebrospinal fluid isolated from the subject. 
     
     
         10 . The method of  claim 9 , wherein the cerebrospinal fluid is lumbar cerebrospinal fluid. 
     
     
         11 . The method of  claim 1 , wherein the agent is a cAMP agonist, a Ca2+ pump inhibitor, a phosphodiesterase inhibitor, a chloride channel activator, an L-type calcium channel blocker, a purinergic agent, an anti-oxidant, a cAMP-activated protein kinase inhibitor, a cathepsin activator, a sirtuin activator, a lipofuscinolytic, a ceroid depletor, an imidazole- 1  receptor agonist, a calpain inhibitor, or an anti-lipolytic agent. 
     
     
         12 . The method of  claim 1 , wherein the agent is a cAMP agonist, Ca2+ pump inhibitor, or a phosphodiesterase inhibitor. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the subject is a mammal. 
     
     
         16 . The method of  claim 1 , wherein the subject is a human. 
     
     
         17 . A method for screening potential compounds or agents to identify a compound or agent that enhances lysosomal activity, the method comprising contacting a population of cells, wherein the cells have impaired lysosomal activity detectable by elevated lysosomal pH or reduced activity of at least three lysosomal proteases, with at least one potential compound or agent and assessing the ability of the at least one potential compound or agent to enhance lysosomal activity in the cells of the population, wherein if contact with the at least one potential compound or agent enhances lysosomal activity relative to contact with a control compound or agent, the at least one potential compound or agent is identified as compound or agent that enhances lysosomal activity. 
     
     
         18 . The method of  claim 17 , wherein the population of cells is isolated from a subject with Alzheimer's Disease (AD). 
     
     
         19 . The method of  claim 17 , wherein the elevated pH is equal to or greater than about 5.2. 
     
     
         20 . The method of  claim 17 , wherein the at least three lysosomal proteases having reduced activity are selected from the group consisting of cathepsin B, cathepsin D, and cathepsin L. 
     
     
         21 . The method of  claim 1 , wherein the agent is a chloride channel activator.

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