Methods of treating schizophrenia and other neuropsychiatric disorders
The present disclosure is directed to methods of restoring glial cell K + uptake in a subject. This method involves selecting a subject having impaired glial cell K + uptake, and administering, to the selected subject, a RE1-Silencing Transcription factor (REST) inhibitor under conditions effective to restore glial cell K + uptake. Subjects having impaired glial cell K + uptake include those at risk of having or having a neuropsychiatric disease or disorder.
1 . A method of restoring K + uptake in human glial cells having decreased K + uptake, said method comprising:
selecting a population of human glial cells having decreased K + uptake and
administering, to the human glial cells having decreased K + uptake, an inhibitor of RE1-Silencing Transcription factor (REST) selective gene expression under conditions effective to restore K + uptake by said human glial cells, wherein the inhibitor comprises an inhibitory nucleic acid molecule selected from the group consisting of a REST antisense oligonucleotide, a REST shRNA, and a REST siRNA,
wherein the inhibitor is packaged in a delivery vehicle that comprises a glial cell targeting moiety.
2 . A method of restoring glial cell K + uptake in a human subject, said method comprising:
selecting a human subject having decreased glial cell K + uptake, and
administering, to the human subject, an inhibitor of RE1-Silencing Transcription factor (REST) selective gene expression under conditions effective to restore glial cell K + uptake, wherein the inhibitor comprises an inhibitory nucleic acid molecule selected from the group consisting of a REST antisense oligonucleotide, a REST shRNA, and a REST siRNA,
wherein the inhibitor is packaged in a delivery vehicle that comprises a glial cell targeting moiety.
3 . The method of claim 2 , wherein the glial cells are glial progenitor cells and said administering is carried out under conditions effective to restore glial progenitor cell derived astrocytic differentiation in the subject.
4 . The method of claim 2 , wherein the glial cells are astrocytes and said administering is carried out under conditions effective to restore astrocyte K + homeostasis.
5 . The method of claim 2 , wherein the selected human subject has or is at risk of having a neuropsychiatric disorder.
6 . The method of claim 5 , wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, autism spectrum disorder, and bipolar disorder.
7 . The method of claim 2 , wherein said administering is carried out under conditions effective to decrease neuronal excitability in said human subject.
8 . The method of claim 2 , wherein said administering is carried out under conditions effective to decrease seizure incidence in said human subject.
9 . The method of claim 2 , wherein the delivery vehicle comprises a viral vector.
10 . A method of treating a neuropsychiatric disorder in a human subject, said method comprising:
selecting a human subject having decreased glial cell K + uptake and the neuropsychiatric disorder, and
administering, to the human subject, an inhibitor of REST selective gene expression under conditions effective to treat the neuropsychiatric disorder in the human subject, wherein the inhibitor comprises an inhibitory nucleic acid molecule selected from the group consisting of a REST antisense oligonucleotide, a REST shRNA, and a REST siRNA, and
wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, autism spectrum disorder, and bipolar disorder.
11 . The method of claim 10 , wherein the inhibitor is packaged in a delivery vehicle.
12 . The method of claim 11 , wherein the delivery vehicle comprises a glial cell targeting moiety.
13 . The method of claim 11 , wherein the delivery vehicle comprises a viral vector.
14 . The method of claim 10 , wherein said administering is carried out under conditions effective to decrease neuronal excitability in said subject.
15 . The method of claim 10 , wherein said administering is carried out under conditions effective to decrease seizure incidence in said human subject.