Methods for treating apolipoprotein e4-associated disorders

Abstract

The present disclosure provides a method of increasing the functionality of a GABAergic interneuron in the hilus of the hippocampus of an individual having at least one apolipoprotein E4 (apoE4) allele. The method generally involves reducing tau levels in the interneuron.

1 . A method of increasing the functionality of a GABAergic interneuron in the hilus of the hippocampus of an individual having at least one apolipoprotein E4 (apoE4) allele, the method comprising reducing the level of tau in the interneuron. 
     
     
         2 . The method of  claim 1 , wherein said reducing comprises administering to the individual a tau-specific interfering nucleic acid that reduces the level of a tau polypeptide in the GABAergic interneuron. 
     
     
         3 . The method of  claim 1 , wherein said tau-specific interfering nucleic acid is encoded by a nucleotide sequence operably linked to a neuron-specific transcriptional control element, wherein the nucleotide sequence is present in a recombinant expression vector. 
     
     
         4 . The method of  claim 2 , wherein said administering is via a local route of administration. 
     
     
         5 . The method of  claim 4 , wherein said administering is via intracranial administration. 
     
     
         6 . The method of  claim 1 , wherein said reducing comprises administering to the individual a genetically modified stem cell that has a reduced level of tau. 
     
     
         7 . The method of  claim 6 , wherein the genetically modified stem cell has a knockout of an endogenous tau-encoding nucleic acid. 
     
     
         8 . The method of  claim 6 , wherein the genetically modified stem cell is generated from a host cell from a donor individual who is the same as the individual being treated. 
     
     
         9 . The method of  claim 6 , wherein the genetically modified stem cell is generated from a host cell from a donor individual who is other than the individual being treated. 
     
     
         10 . The method of  claim 6 , wherein said genetically modified stem cell is a genetically modified induced pluripotent stem cell. 
     
     
         11 . The method of  claim 6 , wherein said genetically modified stem cell is a genetically modified neural stem cell (NSC). 
     
     
         12 . The method of  claim 11 , wherein the genetically modified NSC is an induced NSC (iNSC). 
     
     
         13 . The method of  claim 12 , wherein the iNSC is induced from a somatic cell obtained from the individual being treated. 
     
     
         14 . The method of  claim 1 , wherein said increasing the functionality of a GABAergic interneuron results in an increase in cognitive function in the individual. 
     
     
         15 . The method of  claim 14 , wherein said cognitive function is learning or memory. 
     
     
         16 . A genetically modified stem cell that exhibits reduced production of a tau polypeptide compared to a parent stem cell. 
     
     
         17 . The genetically modified stem cell of  claim 16 , wherein said genetically modified stem cell is a neural stem cell. 
     
     
         18 . The genetically modified stem cell of  claim 17 , wherein said genetically modified stem cell is an induced neural stem cell.