METHODS FOR TREATING APOLIPOPROTEIN E4-ASSOCIATED DISORDERS
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.