Agents that reduce neuronal overexcitation

Abstract

The present invention provides methods of identifying candidate agents for treating excitotoxicity-related disorders. The present invention further provides methods for treating excitotoxicity-related disorders.

1 . An in vitro method of identifying a candidate agent for the treatment of an excitotoxicity-related disorder, the method comprising:
 a) contacting a cell that produces a tau gene product with a test agent in vitro; and   b) determining the effect, if any, of the test agent on the level of the tau gene product in the cell, wherein a test agent that reduces the level of the tau gene product in the cell is a candidate agent for the treatment of an excitotoxicity-related disorder.   
     
     
         2 . The method of  claim 1 , wherein the cell is a neuronal cell. 
     
     
         3 . The method of  claim 2 , wherein the tau gene product is a tau polypeptide, and wherein the level of the tau polypeptide is detected using an immunological assay. 
     
     
         4 . The method of  claim 3 , wherein the effect of the test agent on the level of tau polypeptide is independent of the phosphorylation state of the tau polypeptide and is independent of the solubility state of the tau polypeptide. 
     
     
         5 . The method of  claim 3 , wherein the tau polypeptide is a non-hyperphosphorylated tau polypeptide. 
     
     
         6 . The method of  claim 3 , wherein the tau polypeptide is a soluble tau polypeptide. 
     
     
         7 . The method of  claim 1 , wherein the tau gene product is a fusion protein comprising tau and a polypeptide that provides a detectable signal, and wherein the level of tau is detected by detecting a level of the signal. 
     
     
         8 . The method of  claim 7 , wherein the polypeptide that provides a detectable signal is a fluorescent protein, a chemiluminescent protein, or an enzyme that produces a detectable product. 
     
     
         9 . The method of  claim 1 , wherein the tau gene product is a tau nucleic acid, and wherein the level of the tau nucleic acid is detected using a nucleic acid amplification-based assay. 
     
     
         10 . The method of  claim 1 , wherein the tau gene product is a tau nucleic acid, and wherein the level of the tau nucleic acid is detected using a nucleic acid hybridization assay. 
     
     
         11 . The method of  claim 1 , wherein the tau gene product is encoded by a wild-type tau allele. 
     
     
         12 . An in vivo method of identifying a candidate agent for the treatment of an excitotoxicity-related disorder, the method comprising:
 a) administering a test agent to a non-human animal model for an excitotoxicity-related disorder; and   b) determining the effect, if any, of the test agent on the level of the tau gene product in a cell or a tissue in the animal, wherein a test agent that reduces the level of the tau gene product in the cell or tissue is a candidate agent for the treatment of an excitotoxicity-related disorder.   
     
     
         13 . The method of  claim 12 , further comprising determining the effect, if any, of the test agent on one or more of the level of a calcium-dependent gene product; the number and/or severity and/or frequency of seizures; and a behavioral deficit associated with an excitotoxicity-related disorder. 
     
     
         14 . A method of reducing excitotoxicity in response to a neuronal overstimulation in a neuron in an individual, the method comprising administering to the individual an agent that reduces the level of a tau gene product in the neuron, wherein the agent comprises a nucleic acid that selectively reduces the level of tau gene product in the neuron. 
     
     
         15 . The method of  claim 14 , wherein the tau gene product is encoded by a wild-type tau allele. 
     
     
         16 . The method of  claim 14 , wherein the tau gene product is a tau mRNA. 
     
     
         17 . The method of  claim 14 , wherein the tau gene product is a tau polypeptide. 
     
     
         18 . The method of  claim 16 , wherein the tau polypeptide is a non-hyperphosphorylated, soluble tau polypeptide 
     
     
         19 . A method of treating an excitotoxicity-related disorder in an individual, the method comprising administering to the individual an agent that reduces the level of a tau gene product in a neuron in the individual, wherein the agent comprises a nucleic acid that selectively reduces the level of tau gene product in the neuron. 
     
     
         20 . The method of  claim 19 , wherein the excitotoxicity-related disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, Parkinson's disease, and seizure. 
     
     
         21 . The method of  claim 19 , wherein the tau gene product is encoded by a wild-type tau allele. 
     
     
         22 . The method of  claim 19 , wherein the tau gene product is a tau mRNA. 
     
     
         23 . The method of  claim 19 , wherein the tau gene product is a tau polypeptide. 
     
     
         24 . The method of  claim 23 , wherein the tau polypeptide is a non-hyperphosphorylated, soluble tau polypeptide. 
     
     
         25 . The method of  claim 19 , further comprising administering an effective amount of at least one additional therapeutic agent. 
     
     
         26 . A pharmaceutical composition comprising:
 a) a nucleic acid agent that specifically reduces the level of a tau gene product in a cell; and   b) a pharmaceutically acceptable excipient.   
     
     
         27 . The composition of  claim 26 , wherein the pharmaceutically acceptable excipient comprises an agent that provides for crossing the blood-brain barrier. 
     
     
         28 . The composition of  claim 26 , wherein the tau gene product is encoded by a wild-type tau allele.