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Genes and Pathways Differentially Expressed in Bipolar Disorder And

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Genes and Pathways Differentially Expressed in Bipolar Disorder And (19) TZZ ¥Z _T (11) EP 2 453 024 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) G01N 33/53 (2006.01) 06.12.2017 Bulletin 2017/49 A61K 31/713 (2006.01) A61K 38/00 (2006.01) A61K 48/00 (2006.01) (21) Application number: 11175854.6 (22) Date of filing: 21.06.2005 (54) Genes and pathways differentially expressed in bipolar disorder and/or major depressive disorder Differenziell exprimierte Gene und Leitungsbahnen bei bipolarer Störung und/oder schwerer depressiver Erkrankung Gènes et voies exprimés différemment dans le trouble bipolaire et/ou le trouble dépressif majeur (84) Designated Contracting States: • Lopez, Juan F. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Ann Arbor, MI Michigan MI 48108 (US) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • Lyons, David M. Palo Alto, CA California CA 94025 (US) (30) Priority: 21.06.2004 US 581998 P • Myers, Richard M. 22.10.2004 US 621252 P Stanford, CA California CA 94305 (US) 31.03.2005 US 667296 P • Schatzberg, Alan F. Los Altos, CA California CA 94024 (US) (43) Date of publication of application: • Stein, Richard 16.05.2012 Bulletin 2012/20 Irvine, CA 92620 (US) • Thompson, Robert C. (62) Document number(s) of the earlier application(s) in Ann Arbor, MI Michigan MI 48108 (US) accordance with Art. 76 EPC: • Tomita, Hiroaki 05762518.8 / 1 766 077 Sendai 989-3201 (JP) • Vawter, Marquis P. (73) Proprietor: The Board of Trustees of the Laguna Niguel, CA California CA 92677 (US) Leland Stanford Junior University • Watson, Stanley J. Palo Alto, CA 94306-1106 (US) Ann Arbor, MI Michigan MI 48105 (US) • Turner, Cortney A. (72) Inventors: Willis • Molnar, Margherita MI 48191 (US) Davis, CA California CA 95616 (US) • Akil, Huda (74) Representative: Brasnett, Adrian Hugh Ann Arbor, MI Michigan MI 48105 (US) Mewburn Ellis LLP • Bunney, William E. City Tower Laguna Beach, CA California CA 92651 (US) 40 Basinghall Street • Choudary, Prabhakara V. London EC2V 5DE (GB) Davis, CA California CA 95616 (US) • Evans, Simon J. (56) References cited: Milan, MI Michigan MI 48160 (US) WO-A-2004/047727 WO-A2-2004/043395 • Jones, Edward G. Winters, CA California CA 95694 (US) • Li, Jun Palo Alto, CA California CA 94306 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 453 024 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 453 024 B1 • EVANSS J ET AL: "Dysregulation of the fibroblast • ELYSE L. AURBACH ET AL: "Fibroblast growth growth factor system in major depression", factor 9 is a novel modulator of negative affect", PROCEEDINGS OF THE NATIONAL ACADEMY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF OF SCIENCES, vol. 112, no. 38, 8 September 2015 AMERICA, vol. 101, no. 43, 26 October 2004 (2015-09-08), pages 11953-11958, XP55276886, (2004-10-26), pages 15506-15511, XP002462754, US ISSN: 0027-8424, DOI: ISSN: 0027-8424 10.1073/pnas.1510456112 • KNUUTTILA JUHA E A ET AL: "Effects of antidepressant drug imipramine on gene Remarks: expression in rat prefrontal cortex", Thefile contains technical information submitted after NEUROCHEMICAL RESEARCH, vol. 29, no. 6, 1 the application was filed and not included in this June 2004 (2004-06-01), pages 1235-1244, specification XP002671425, ISSN: 0364-3190 • LANDGREBE J ET AL: "Molecular characterisation of antidepressant effects in the mouse brain using gene expression profiling", JOURNAL OF PSYCHIATRIC RESEARCH, ELSEVIER LTD, GB, vol. 36, no. 3, 1 May 2002 (2002-05-01), pages119-129, XP027248092, ISSN: 0022-3956 [retrieved on 2002-05-01] 2 EP 2 453 024 B1 Description BACKGROUND OF THE INVENTION 5 [0001] Clinical depression, including both bipolar disorders and major depression disorders, is a major public health problem, affecting an estimated 9.5% of the adult population of the United States each year. While it has been hypoth- esized that mental illness, including mood disorders such as major depression ("MDD") and bipolar disorder ("BP") as well as psychotic disorders such as schizophrenia, may have genetic roots, little progress has been made in identifying gene sequences and gene products that play a role in causing these disorders, as is true for many diseases with a 10 complex genetic origin (see, e.g., Burmeister, Biol. Psychiatry 45:522-532 (1999)). [0002] The current lack of biomarkers and the ineffectiveness and reliability of the diagnosis and rates are important issues for the treatment of mental disorders. For example, around 15% of the population suffers from MDD while ap- proximately 1% suffers from BP disorders. Diagnosing bipolar disorder is difficult when, as sometimes occurs, the patient presents only symptoms of depression to the clinician. At least 10-15% of BP patients are reported to be misdiagnosed 15 as MDD. The consequences of such misdiagnosis include a delay in being introduced to efficacious treatment with mood stabilizers and a delay in seeking or obtaining counseling specific to bipolar disorder. Also treatment with antidepressants alone induces rapid cycling, switching to manic or mixed state, and consequently increases suicide risk. Furthermore, in addition to a lack of efficacy, long onset of action and side effects (sexual, sleep, weight gain, etc.), there are recent concerns relating to the undesirable effects of ADs on metabolic syndromes, such as diabetes and hypercholesteremia. 20 BRIEF SUMMARY OF THE INVENTION [0003] Relying on the discovery that certain genes expressed in particular brain pathways and regions are likely involved in the development of mental illness, the present invention provides compounds for use in treatment of mental 25 illness. Also described are methods for identifying compounds effective in treating mental illness. [0004] In order to further understand the neurobiology of mood disorders such as bipolar disorders (BP) and major depression disorders (MDD), the inventors of the present application have used DNA microarrays to study expression profiles of human post-mortem brains from patients diagnosed with BP or MDD. In one aspect, described is differential gene expression in the Anterior Cingulate (AnCg), Dorsolateral Prefrontal (DLPFC), and Cerebellar (CB) cortices, Hip- 30 pocampus, NucleusAccumbens and Amygdala regions ofthe brain, whereinthe differential geneexpression isassociated with Bipolar Disorder (BPD) and Major Depressive Disorder (MDD). Certain genes in these regions are considered "unique" to a given disorder such as BP or MDD when differentially expressed in a particular mood disorder and not another (see, e.g., Tables 3, 4, 14-20). In other cases, where the genes are differentially expressed in both BP and MDD relative to healthy controls, the genes are considered to be involved in both disorders. Expression of the differentially 35 expressed genes may be detected using any suitable methods of detection, e.g., microarrays, PCR or in situ hybridization. Gene expression may be detected in brain tissue, brain tissue samples, or other tissue samples (e.g., blood samples in the case of NCAM1). [0005] In one case, this description relates to differential gene expression associated with G protein-coupled receptors (GPCR)s and downstream signaling pathways, mediated by cyclic adenosine monophosphate (cAMP) and phosphati- 40 dylinositol (PI), wherein the gene expression differentially occurs in the Anterior Cingulate (AnCg), Dorsolateral Prefrontal (DLPFC), and Cerebellar (CB) cortices, Hippocampus, Nucleus Accumbens and Amygdala regions of the brains of patients with Bipolar Disorder (BPD) and/or Major Depressive Disorder (MDD), relative to healthy controls (see, e.g., Tables 14-20). [0006] In another case, this description relates to differential gene expression associated with G protein-coupled 45 receptors (GPCR)s and downstream signaling pathways, mediated by cyclic adenosine monophosphate (cAMP) and phosphatidylinositol (PI), wherein the gene expression differentially occurs in the Hippocampus, Nucleus Accumbens and Amygdala regions of the brains of patients with Bipolar Disorder (BPD) and/or Major Depressive Disorder (MDD), relative to healthy controls (see, e.g., Tables 18-20). [0007] The present disclosure also demonstrates differential expression of the FGF pathway in the frontal cortex of 50 MDD subjects. Particular FGF-related genes, such as FGF2, are dysregulated by antidepressant therapy, environmental complexity, and the correlation to anxiety-like behavior (see, e.g., Tables 1a, 1b, and 2, and Figures 1-7 and 22). The FGF pathway is also related to neurogenesis, e.g., neural stem cell proliferation and differentiation, and the genes disclosed herein can be used for diagnosis and therapeutics related to neurogenesis. Furthermore, Figure 23 shows the effects of postnatal FGF-2 adminstration on neurogenesis, emotionality and gene expression in adult rats. The FGF 55 injected animals exhibit significantly increased cell survival and proliteration in the dentate gyrus of the hippocampus. As adults, the animals show higher locomotor activity in a novel environment, an index of lower anxiety, and have better learning and memory. [0008] The present disclosure also demonstrates that the genes of the glutamate/GABA signaling pathways are in- 3 EP 2 453 024 B1 volved in MDD and BP (see Figure 24 and Table 8). [0009] The present disclosure also demonstrates that mitrochondrial genes are involved in MDD andBP (see Table 10). [0010] The present disclosure also demonstrates that 40 genes encoding growth factor family members and growth factor receptors are significantly differentially expressed in BP or MDD in the DLPFC or AnCg (see Tables 5, 6 and 7).
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