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(12) Patent Application Publication (10) Pub. No.: US 2011/0098188 A1 Niculescu Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0098188 A1 Niculescu Et Al US 2011 0098188A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0098188 A1 Niculescu et al. (43) Pub. Date: Apr. 28, 2011 (54) BLOOD BOMARKERS FOR PSYCHOSIS Related U.S. Application Data (60) Provisional application No. 60/917,784, filed on May (75) Inventors: Alexander B. Niculescu, Indianapolis, IN (US); Daniel R. 14, 2007. Salomon, San Diego, CA (US) Publication Classification (51) Int. Cl. (73) Assignees: THE SCRIPPS RESEARCH C40B 30/04 (2006.01) INSTITUTE, La Jolla, CA (US); CI2O I/68 (2006.01) INDIANA UNIVERSITY GOIN 33/53 (2006.01) RESEARCH AND C40B 40/04 (2006.01) TECHNOLOGY C40B 40/10 (2006.01) CORPORATION, Indianapolis, IN (52) U.S. Cl. .................. 506/9: 435/6: 435/7.92; 506/15; (US) 506/18 (57) ABSTRACT (21) Appl. No.: 12/599,763 A plurality of biomarkers determine the diagnosis of psycho (22) PCT Fled: May 13, 2008 sis based on the expression levels in a sample Such as blood. Subsets of biomarkers predict the diagnosis of delusion or (86) PCT NO.: PCT/US08/63539 hallucination. The biomarkers are identified using a conver gent functional genomics approach based on animal and S371 (c)(1), human data. Methods and compositions for clinical diagnosis (2), (4) Date: Dec. 22, 2010 of psychosis are provided. Human blood Human External Lines Animal Model External of Evidence changed in low vs. high Lines of Evidence psychosis (2pt.) Human postmortem s Animal model brai brain data (1 pt.) > Cite go data (1 p. Biomarker For Bonus 1 pt. Psychosis Human genetic 2 N linkage? association A all model blood data (1 pt.) data (1 p. Changes due to Changes due to genetic psychiatric inheritance medication NY Changes due to environmental factors Patent Application Publication Apr. 28, 2011 Sheet 1 of 5 US 2011/0098188A1 Human blood Human External Lines Animal Model External of Evidence changed in low vs. high Lines of Evidence psychosis (2pt.) Bonus 2 pt. Animal model brain Candidate data (1 pt.) Blood Biomarker For Bonus 1 pt. Psychosis Human genetic linkage/association data (1 pt.) FIG. 1A Changes due to genetic inheritance Changes due to environmental factors FIG. 1B Patent Application Publication Apr. 28, 2011 Sheet 2 of 5 US 2011/0098188A1 Patent Application Publication Apr. 28, 2011 Sheet 3 of 5 US 2011/0098188A1 US 2011/0098188 A1 Apr. 28, 2011 BLOOD BOMARKERS FOR PSYCHOSIS the sample size used is often Small. Given the genetic hetero geneity in human samples and the effects of illness state and CROSS REFERENCE TO RELATED environmental history, including medications and drugs, on APPLICATIONS gene expression, it may not be reliable to extract bona fide findings. 2) Use of lymphoblastoid cell lines—passagedlym 0001. This application claims priority to U.S. provisional phoblastoid cell lines provide a self-renewable source of application Ser. No. 60/917,784, filed May 14, 2007, the material, and are purported to avoid the effects of environ disclosure of which is hereby incorporated by reference in its mental exposure of cells from fresh blood. Fresh blood, how entirety. ever, with phenotypic state information gathered at time of 0002 Part of the work during the development of this harvesting, may be more informative than immortalized lym invention was made with government Support from the phocytes, and may avoid some of the caveats of Epstein-Barr National Institutes of Health under grant NIMH R01 virus (EBV) immortalization and cell culture passaging. MH071912-01. The U.S. Government has certain rights in 0007. The current state of the understanding of the genetic the invention. and neurobiological basis for psychotic disorders in general and of peripheral molecular biomarkers of the illness in par BACKGROUND ticular, is still inadequate. Almost all of the fundamental 0003 Research into the biological basis of psychotic dis genetic, environmental, and biological elements needed to orders (such as Schizophrenia and schizoaffective disorder) delineate the etiology and pathophysiology of psychotic dis has been primarily focused in human and animal studies orders are yet to be completely identified, understood and mostly independently. The two avenues of research have validated. One of the rate-limiting steps has been the lack of complementary strengths and weaknesses. In human genetic concerted integration across disciplines and methodologies. studies, for example, in samples of patients with psychotic The use of a multidisciplinary, integrative research frame disorders and their family members, positional cloning meth work as in the present disclosure provided herein, should lead ods such as linkage analysis, linkage-disequilibrium map to a reduction in the historically high rate of inferential errors ping, and candidate-gene association analysis are narrowing committed in studies of complex diseases like psychotic dis the search for the chromosomal regions harboring risk genes orders. for the illness and, in some cases, identifying plausible can 0008 Identification and validation of peripheral biomark didate genes and polymorphisms that will require further ers for psychotic disorders have proven arduous, despite validation. Human postmortem brain gene expression studies recent large-scale efforts. Human genomic studies are sus have also been employed as a way of trying to identify can ceptible to the issue of being underpowered, due to genetic didate genes for psychotic disorders. In general, human stud heterogeneity, the effect of variable environmental exposure ies suffer from issues of sensitivity—the signal is often diffi on gene expression, and difficulty of accrual of large samples. cult to detect due to the noise generated by the genetic Animal model gene expression studies, in a genetically heterogeneity of individuals and the effects of diverse envi homogeneous and experimentally tractable setting, can avoid ronmental exposures on gene expression and phenotypic pen artifacts and provide sensitivity of detection. Subsequent etrance. comparisons of the animal datasets with human genetic and 0004 Inanimal studies, carried out in isogenic strains with genomic datasets can ensure cross-validatory power and controlled environmental exposure, the identification of puta specificity. tive neurobiological Substrates of psychotic disorders is typi 0009 Convergent functional genomics (CFG), is an cally accomplished by modeling human psychotic disorders approach that translationally cross-matches animal model through pharmacological or genetic manipulations. Animal gene expression data with human genetic linkage data and model studies suffer from issues of specificity—questions human tissue data (blood, postmortem brain), as a Bayesian regarding direct relevance to the human disorder modeled. strategy of cross validating findings and identifying candidate Each independent line of investigation (i.e., human and ani genes, pathways and mechanisms for neuropsychiatric disor mal studies) is contributing to the incremental gains in knowl ders. Predictive biomarkers for psychosis are desired for edge of psychotic disorders etiology witnessed in the last clinical diagnosis and treatment purposes. The present dis decade. closure provides several biomarkers that are predictive of 0005. However, a lack of integration between these two psychotic disorders in clinical settings. lines of investigations hinders Scientific understanding and 0010 No objective clinical laboratory blood tests for psy slows the pace of discovery. Psychiatric phenotypes, as cur chosis is available. The current reliance on patient self-report rently defined, are primarily the result of clinical consensus of symptom severity and on the clinicians' impression alone criteria rather than empirical determination. The present dis are rate limiting steps in effective treatment, and in new drug closure provides methods and compositions that empirically development. Blood biomarkers for psychosis state provide determine disease states for diagnosis and treatment. useful tools for diagnosis and therapy. 0006 Objective biomarkers of illness and treatment response would make a significant difference in the ability to SUMMARY diagnose and treat patients with psychotic disorders, elimi nating Subjectivity and reliance of patient's self-report of 0011 Methods and compositions to clinically diagnose symptoms. Blood gene expression profiling has emerged as a psychotic disorders using a panel of biomarkers are disclosed. particularly interesting area of research in the search for A panel of biomarkers may include 1 to about 100 or more peripheral biomarkers. Most of the studies to date have biomarkers. The panel of biomarkers includes one or more focused on human lymphocytes gene expression profiling, biomarkers for psychosis. Blood is a suitable sample for comparison between illness groups and normal controls. measuring the levels or presence of one or more of the biom They suffer from one of both of the following limitations: 1) arkers provided herein. US 2011/0098188 A1 Apr. 28, 2011 0012. In an aspect, psychotic symptoms measured in a subset of about 10 biomarkers for hallucinations designated quantitative fashion at time of blood draw in human Subjects as Rhobtb3, Aldh111, Mpp3, Fn1, Spp 1, Arhgef), S100a6, focus on all or nothing phenomena (genes turned on and offin Adamts5, Pdap1, and Plxnd 1. low symptom states VS. high symptom states). Some of the 0021. A suitable sample is blood. The level of the biom biomarkers have cross-matched animal and human data, arker can also be determined in a tissue biopsy sample of the using a convergent
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