Targets, methods, and reagents for diagnosis and treatment of schizophrenia
First Claim
1. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
- (i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting a polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or detecting a polymorphic variant of a polymorphism in a genomic region linked to such a gene, in the sample.
3 Assignments
0 Petitions
Accused Products
Abstract
The present invention provides targets, methods, and reagents for the diagnosis and treatment of schizophrenia and related conditions. The invention provides methods for the diagnosis of schizophrenia and susceptibility to schizophrenia by detection of polymorphisms, mutations, variations, alterations in expression, etc., in calcineurin genes or calcineurin interacting genes, or polymorphisms linked to such genes. The invention provides oligonucleotides, arrays, and antibodies for detection of polymorphisms and variants. The invention provides transgenic mice having alterations in such genes. The invention also provides methods of treating schizophrenia by administering compounds that target these genes. The invention further provides screening methods for identifying such compounds and compounds obtained by perfoming the screens.
-
Citations
170 Claims
-
1. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
-
(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting a polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or detecting a polymorphic variant of a polymorphism in a genomic region linked to such a gene, in the sample. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 73, 123)
-
-
21. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
-
(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting an alteration or variation in expression or activity of a calcineurin subunit or a calcineurin interacting molecule in the sample, relative to the expression or activity of the calcineurin subunit or calcineurin interacting molecule that would be expected in a sample obtained from a normal subject. - View Dependent Claims (22, 23, 24, 25)
-
-
26. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:
-
(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and
(ii) detecting an alteration or variation in a calcineurin subunit or a calcineurin interacting molecule in the sample. - View Dependent Claims (27, 28, 29, 30, 31)
-
-
32. A method for treating schizophrenia or susceptibility to schizophrenia comprising:
-
providing a subject at risk of or suffering from schizophrenia; and
administering a compound that modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule to the subject. - View Dependent Claims (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
-
-
62. A method for treating schizophrenia or susceptibility to schizophrenia comprising:
-
providing a subject at risk of or suffering from schizophrenia; and
administering a compound that modulates intracellular calcium levels to the subject. - View Dependent Claims (63, 65, 66, 67, 68, 69)
-
-
64. A method for treating schizophrenia or susceptibility to schizophrenia comprising:
-
providing a subject at risk of or suffering from schizophrenia; and
administering a compound that modulates hippocampal or cortical LTD to the subject.
-
-
70. A method for treating schizophrenia or susceptibility to schizophrenia comprising:
-
providing a subject at risk of or suffering from schizophrenia; and
administering a compound that modulates expression or activity of one or more NFAT-regulated proteins.
-
-
71. A method for treating an immune system condition in a subject having schizophrenia or susceptibility to schizophrenia comprising:
-
providing a subject at risk of or suffering from an immune system abnormality and at risk of or suffering from schizophrenia; and
administering a compound that modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule to the subject. - View Dependent Claims (72)
-
-
74. A method of identifying a polymorphism useful in diagnosis of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
identifying one or more polymorphisms in or linked to a gene encoding a CN subunit or CN interacting protein;
providing a set of samples including samples obtained from subjects affected with schizophrenia;
testing the samples for linkage or association of one or more variants of the polymorphism with schizophrenia; and
identifying the polymorphism as useful in diagnosis of schizophrenia if linkage of association between one or more variants of the polymorphism and schizophrenia susceptibility.
-
-
75. A method of identifying a mutation that contributes to or causes schizophrenia or susceptibility to schizophrenia comprising steps of:
-
identifying a polymorphism in or linked to a gene encoding a CN subunit or CN interacting protein;
determining that a polymorphic variant of the polymorphism is linked to or associated with susceptibilty to schizophrenia;
sequencing the gene and optionally regulatory regions of the gene in a sample obtained from one or more subjects suffering from schizophrenia;
comparing the sequence obtained with a normal or wild type sequence of the same gene;
identifying the polymorphic variant as representing a mutation that causes or contributes to schizophrenia if the sequence obtained in the sequencing step differs from the normal or wild type sequence.
-
-
76. A method for identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising NF-AT, calcineurin, and an NF-AT reporter;
contacting the biological system with a compound;
comparing the transcriptional response of the reporter in the presence of the compound with the response or expected response in the absence of the compound; and
identifying the compound as a a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the transcriptional response in the presence of the compound is different from the transcriptional response that occurs or would be expected in the absence of the compound. - View Dependent Claims (77, 78, 79)
-
-
80. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising phosphorylated calcineurin substrate and calcineurin;
contacting the biological system with a compound;
comparing the extent or rate of dephosphorylation of the substrate with the extent or rate of dephosphorylation occurring or expected to occur in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of dephosphorylation in the presence of the compound is different from the extent or rate of dephosphorylation that occurs or would be expected in the absence of the compound. - View Dependent Claims (81, 82)
-
-
83. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising a cellular membrane comprising ryanodine receptor type 3;
contacting the biological system with a compound;
contacting the cellular membrane with ryanodine;
comparing the extent or rate of binding of ryanodine to the cellular membrane in the presence of the compound with the extent or rate of binding that occurs or would be expected in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding in the presence of the compound is different from that occurring or expected to occur in the absence of the compound. - View Dependent Claims (84, 85)
-
-
86. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising a cellular membrane comprising IP3 receptor type 1;
contacting the biological system with a compound;
contacting the cellular membrane with IP3;
comparing the extent or rate of binding of IP3 to the cellular membrane in the presence of the compound with the extent or rate of binding that occurs or would be expected in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding in the presence of the compound is different from that occurring or expected to occur in the absence of the compound. - View Dependent Claims (87, 88)
-
-
89. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising a transcriptional reporter construct, wherein the construct comprises a PP1-responsive regulatory element;
contacting the biological system with the compound;
comparing transcriptional response of the reporter in the presence of the compound with the response or expected response in the absence of the compound; and
identifying the compound as a modulator of PP1 activity if the transcriptional response in the presence of the compound is different from the transcriptional response that occurs or would be expected in the absence of the compound. - View Dependent Claims (90, 91, 92)
-
-
93. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising calcineurin and an endogenous calcineurin inhibitor;
contacting the biological system with the compound;
comparing extent or rate of binding of calcineurin and the endogenous calcineurin inhibitor in the presence of the compound with the extent or rate of binding that occurs or would be expected to occur in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding of calcineurin and the endogenous calcineurin inhibitor in the presence of the compound is different from the extent or rate of binding that occurs or would be expected in the absence of the compound. - View Dependent Claims (94)
-
-
95. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system comprising calcineurin and calmodulin;
contacting the biological system with the compound;
comparing extent or rate of binding of calcineurin and calmodulin in the presence of the compound with the extent or rate of binding that occurs or would be expected to occur in the absence of the compound; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding of calcineurin and calmodulin in the presence of the compound is different from the extent or rate of binding that occurs or would be expected in the absence of the compound. - View Dependent Claims (96, 97)
-
-
98. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system suitable for measuring LTD;
contacting the biological system with the candidate compound;
measuring LTD in the biological system; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent of LTD in the biological system from the extent of LTD that occurs or would be expected to occur in the absence of the compound. - View Dependent Claims (99)
-
-
100. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:
-
providing a biological system suitable for measuring intracellular calcium;
contacting the biological system with the candidate compound;
measuring intracellular calcium or calcium flux in the biological system; and
identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the level of intracellular calcium or calcium flux in the biological system differs from the level of intracellular calcium or calcium flux that occurs or would be expected to occur in the absence of the compound. - View Dependent Claims (101, 102, 104, 118, 119, 120, 121, 122)
-
-
103. A method for identifying a candidate compound for treatment of schizophrenia or schizophrenia susceptibility comprising steps of:
-
providing a molecular structure of CN or a CN complex;
identifying a structure that is expected to bind to CN or a CN complex or to prevent binding of CN or of a CN subunits either to another CN subunit or to a CN interacting molecule; and
selecting a compound having such a structure as a candidate compound for treatment of schizophrenia or schizophrenia susceptibility.
-
-
105. A method of identifying a compound for treatment of schizophrenia comprising steps of:
-
providing a subject or subjects;
administering a candidate compound to the subject or subjects, wherein the candidate compound modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule;
comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and
identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered.
-
-
106. A method of identifying a compound for treatment of schizophrenia comprising steps of:
-
providing a subject or subjects at risk of or exhibiting one or more phenotypes suggestive of schizophrenia, wherein the subject or subjects have an alteration in at least one calcineurin subunit or calcineurin interacting molecule or in a gene encoding such a molecule;
administering a candidate compound to the subject or subjects;
comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and
identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered. - View Dependent Claims (107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117)
-
- 124. An oligonucleotide designed to specifically detect or amplify a naturally occurring polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.
- 128. An oligonucleotide designed to specifically detect or amplify a naturally occurring nucleic acid region comprising a polymorphic site in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.
-
138. A primer that terminates at the nucleotide position immediately adjacent to a naturally occurring polymorphic site on the 3′
- side and extends at least 8 and less than 100 nucleotides in the 5′
direction from this site, wherein the polymorphic site is the site of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or is the site of a polymorphism in a genomic region linked to such a gene. - View Dependent Claims (139, 140, 141, 142, 143, 144, 145)
- side and extends at least 8 and less than 100 nucleotides in the 5′
- 146. An siRNA molecule targeted to a transcript encoding a calcineurin subunit or calcineurin interacting molecule.
- 153. An antibody that specifically binds to a variant of a calcineurin subunit or calcineurin interacting molecule, wherein the calcineurin subunit or calcineurin interacting molecule is encoded by a gene comprising a polymorphic variant, wherein existence of the polymorphic variant in a subject is indicative of susceptibility to or presence of schizophrenia.
- 159. A transgenic animal having altered expression of CNAγ
-
168. A transgenic mouse, wherein the mouse is a CNB hypomorph.
-
169. A mouse obtained by crossing a mouse having altered expression of CNAγ
- or CNB with a second mouse having altered expression of a CN subunit or CN interacting molecule.
-
170. A database comprising a list of polymorphic sequences stored on a computer-readable medium, wherein the polymorphic sequences occur in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or in a genomic region linked to such a gene, and wherein the list is largely or entirely limited to polymorphisms have been identified as useful in performing genetic diagnosis of schizophrenia or susceptibility to schizophrenia, or for performing genetic studies of schizophrenia or susceptibility to schizophrenia.
Specification