JP-2022511568-A5 -

Dates

Publication Date

20221215

Application Date

20191211

Description

As described herein, targetable signaling nodes capable of mitigating the pathological state of glial cells associated with schizophrenia have been identified. To this end, iPSC GPCs were generated from patients who developed schizophrenia in childhood or from normal controls (CTRs), and astrocytes were produced from these. The patterns of gene expression and functional differentiation of astrocytes from schizophrenia-derived and control-derived GPCs were compared. It was found that excessive TGFβ signaling plays a crucial role in the uncontrolled differentiation of schizophrenia-derived GPCs, that the action of TGFβ in this cellular environment is signaled through SMAD4, and that phenotypic normality can be restored to SCZ glial cells by inhibiting SMAD4. [Invention 1001] A method for restoring K + uptake by glial cells with impaired K + channel function, Administering a SMAD4 inhibitor to glial cells having impaired K + channel function under conditions effective in restoring K + uptake by the glial cells. The method, including the method described above. [Invention 1002] The method of the present invention 1001, wherein the glial cells are glial progenitor cells. [Invention 1003] The method of the present invention 1002, wherein the administration is carried out under conditions that are effective in restoring the differentiation of glial progenitor cells into astrocytes. [Invention 1004] The method of the present invention 1001, wherein the glial cells are astrocytes. [Invention 1005] The method of the present invention 1001, wherein the SMAD4 inhibitor is an inhibitory nucleic acid molecule selected from the group consisting of SMAD4 antisense oligonucleotides, SMAD4 shRNA, and SMAD4 siRNA. [Invention 1006] The method of the present invention 1001, wherein the SMAD4 inhibitor is a small molecule selected from the group consisting of 5-fluorouracil, valproic acid, vorinostat, and PR-629. [Invention 1007] The method of the present invention 1001, wherein the glial cells having impaired K + channel function are glial cells of a subject with a neuropsychiatric disorder. [Invention 1008] The method of the present invention 1008, wherein the neuropsychiatric disorder is schizophrenia. [Invention 1009] A method for restoring K + uptake by glial cells in a subject , Selecting subjects with impaired K + uptake in glial cells , The selected subjects are administered a SMAD4 inhibitor under conditions effective in restoring K + uptake by the glial cells. The method, including the method described above. [Invention 1010] The method of the present invention 1009, wherein the glial cells are glial progenitor cells. [Invention 1011] The method of the present invention 1010, wherein the administration is carried out under conditions that are effective in restoring the differentiation of glial progenitor cells into astrocytes in the subject. [Invention 1012] The method of the present invention 1009, wherein the glial cells are astrocytes. [Invention 1013] The method of the present invention 1012, wherein the administration is carried out under conditions that are effective in restoring K + homeostasis of astrocytes . [Invention 1014] The method of the present invention 1009, wherein the SMAD4 inhibitor is an inhibitory nucleic acid molecule selected from the group consisting of SMAD4 antisense oligonucleotides, SMAD4 shRNA, and SMAD4 siRNA. [Invention 1015] The method of the present invention 1009, wherein the SMAD4 inhibitor is a small molecule selected from the group consisting of 5-fluorouracil, valproic acid, vorinostat, and PR-629. [Invention 1016] The method of the present invention 1009, wherein the SMAD4 inhibitor is packaged in a nanoparticle delivery vehicle. [Invention 1017] The method of the present invention 1015, wherein the delivery vehicle includes a glial cell targeting portion. [Invention 1018] The method of the present invention 1009, wherein the selected subject has or is at risk of having a neuropsychiatric disorder. [Invention 1019] The method of the present invention 1018, wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia, autism spectrum disorder, and bipolar disorder. [Invention 1020] The method of the present invention 1019, wherein the neuropsychiatric disorder is schizophrenia. [Invention 1021] The method of the present invention 1009, wherein the administration is carried out under conditions that are effective in reducing the excitability of nerve cells in the subject. [Invention 1022] The method of the present invention 1009, wherein the administration is carried out under conditions that are effective in reducing the occurrence of seizures in the subject. [Invention 1023] The method of the present invention 1009, wherein the administration is carried out under conditions that are effective in improving cognitive impairment in the subject. [Invention 1024] The method of the present invention 1009, wherein the administration is carried out by intr