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(12) Patent Application Publication (10) Pub. No.: US 2006/0246484 A1 Hare Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0246484 A1 Hare Et Al US 20060246484A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0246484 A1 Hare et al. (43) Pub. Date: Nov. 2, 2006 (54) IDENTIFICATION OF GENE EXPRESSION Related U.S. Application Data BY HEART FAILURE ETOLOGY (60) Provisional application No. 60/660,370, filed on Mar. (76) Inventors: Joshua M. Hare, Baltimore, MD (US); 10, 2005. Michelle M. Kittleson, Los Angeles, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. COHEN, PONTANI, LIEBERMAN & PAVANE CI2O I/68 (2006.01) SS1 FIFTHAVENUE G06F 9/00 (2006.01) SUTE 1210 (52) U.S. Cl. ................................................... 435/6; 702/20 NEW YORK, NY 10176 (US) (57) ABSTRACT (21) Appl. No.: 11/373,812 Differential gene expression profiles identifying heart failure (22) Filed: Mar. 10, 2006 etiology and the use thereof are disclosed. Patent Application Publication Nov. 2, 2006 Sheet 1 of 9 US 2006/0246484 A1 SIG MET CAT CEL BIN NUC TRA INF DEV APO CYT FIGURE 1 Patent Application Publication Nov. 2, 2006 Sheet 2 of 9 US 2006/0246484 A1 Nonfailing FIGURE 2 Patent Application Publication Nov. 2, 2006 Sheet 3 of 9 US 2006/0246484 A1 PHLDA1 TNFRSF11B S100A8 2 O ATP1 B3 SERPINE1 -2 -4 SLC39A8 FIGURE 3 Patent Application Publication Nov. 2, 2006 Sheet 4 of 9 US 2006/0246484 A1 10 NCM-NF ICM-NF NCM-NF ICM-NF FIGURE 3 Patent Application Publication Nov. 2, 2006 Sheet 5 of 9 US 2006/0246484 A1 Patent Application Publication Nov. 2, 2006 Sheet 6 of 9 US 2006/0246484 A1 Patent Application Publication Nov. 2, 2006 Sheet 7 of 9 US 2006/0246484 A1 23.iserwas id - Patent Application Publication Nov. 2, 2006 Sheet 8 of 9 US 2006/0246484 A1 25 SAMPLES TRAINING SET TEST SET 5 No-LVAD samples 7 Pre-LVAD samples 6 No-LVAD samples 7 Pre-LVAD samples FIGURE 7 Patent Application Publication Nov. 2, 2006 Sheet 9 of 9 US 2006/0246484 A1 No-LVAD (NLV) LVAD (LV) FIGURE 8 US 2006/0246484 A1 Nov. 2, 2006 IDENTIFICATION OF GENE EXPRESSION BY cardiac resynchronization therapy, (74-76) implantable HEART FAILURE ETOLOGY defibrillators, (77-79) and ventricular assist devices.(80) 0008 However, it is still not clear which patients will RELATED APPLICATIONS benefit most from which therapies, and a better understand ing of the differences in response to therapy is essential 0001. This application claims priority from U.S. Provi because there are an increasing number of interventions that sional Patent Application Ser. No. 60/660,370 which was may be costly, Such as implantable cardiac defibrillators; filed on Mar. 10, 2005, content of which is incorporated by (81) risky, Such as ventricular assist devices; (80) or scarce, reference in its entirety. Such as donor hearts for cardiac transplantation.(82) BACKGROUND OF THE INVENTION 0009 Thus, it is essential to determine if gene expression profiling through molecular signature analysis can distin 0002) 1. Field of Invention guish between patients at different disease stages. One relevant disease stage is end-stage patients with and without 0003. The present invention relates to a gene expression left ventricular assist devices (LVADs). Patients with end profile, which provides information on heart failure etiology. stage cardiomyopathy who are listed for cardiac transplan 0004 2. Related Art tation all exhibit advanced heart failure. However, those who receive an LVAD prior to transplantation are a unique 0005 Dilated cardiomyopathy is a common cause of Subset: patients who experience circulatory collapse before congestive heart failure, the leading cause of cardiovascular a heart becomes available and who would die if they did not morbidity and mortality in the United States (27). Dilated receive mechanical circulatory Support as a bridge to trans cardiomyopathy can be initiated by a variety of factors. Such plantation. Thus, these two types of end-stage cardiomyopa as ischemia, pressure or Volume overload, myocardial thy patients form opposite ends of the clinical spectrum of inflammation or infiltration, and inherited mutations (14). A advanced heart failure. prevailing hypothesis is that, despite the varied inciting mechanisms that initiate the heart failure syndrome, there is 0010. In this study, we have also shown that molecular a final common pathway that drives heart failure progression signature analysis can be used to distinguish end-stage (47). Because of this, there is limited research into specific cardiomyopathy patients by stage of disease. This work molecular events that are unique to the underlying process. Supports our central hypothesis, that gene expression This issue is especially relevant in the two major forms of molecular signatures can be associated with clinically rel dilated cardiomyopathy, nonischemic (NICM) and ischemic evant parameters in heart failure patients and that these (ICM), While NICM and ICM have similar presentations profiles can be applied prospectively in a diagnostic fashion. (26), they are characterized by different pathophysiology, SUMMARY OF THE INVENTION prognosis, and response to therapy (19; 21; 23; 24; 32: 42), 0011 Cardiomyopathy can be initiated by many factors, and understanding their different pathophysiologic mecha but the pathway from unique inciting mechanisms to the nisms is essential in guiding future therapies. common endpoint of Ventricular dilation and reduced car 0006 The emergence of microarray technology to simul diac output is unclear. We previously described a microar taneously assess mRNA levels of tens of thousands of genes ray-based prediction algorithm differentiating nonischemic offers a novel approach to compare and contrast the myo (NICM) from ischemic (ICM) cardiomyopathy using near cardial transcriptome of NICM and ICM. Although previous est shrunken centroids. Accordingly, we tested the hypoth studies have examined changes in gene expression in failing esis that NICM and ICM would have both shared and versus nonfailing (NF) hearts (2: 5; 44; 45; 51), they have distinct differentially expressed genes relative to normal focused only on NICM. The goal of this study was to hearts and compared gene expression of 21 NICM and 10 simultaneously examine the differences in transcriptomes ICM cardiomyopathy samples with that of 6 nonfailing (NF) between either NICM or ICM and normal hearts to establish hearts using Affymetrix U133A GeneChips and Significance a set of shared and unique genes differentially expressed in Analysis of Microarrays. Compared to NF, 257 genes were the two major causes of heart failure. The present approach differentially expressed in NICM and 72 genes in ICM. Only is distinct, but complementary, to our previous study (33) in 41 genes were shared between the two comparisons, mainly which we used the method of nearest shrunken centroids involved in cell growth and signal transduction. Those (46) to determine a clinical prediction algorithm (i.e. a gene uniquely expressed in NICM were frequently involved in expression-based biomarker) that differentiated between metabolism, and those in ICM more often had catalytic NICM and ICM. The current analysis offers insight into both activity. Novel genes included angiotensin-converting disease-specific pathogenesis and therapeutics. Further enzyme 2 (ACE2), which was upregulated in NICM but not more, an understanding of the distinctions with potential ICM, suggesting that ACE2 may offer differential therapeu pathophysiologic underpinnings between these two condi tic efficacy in NICM and ICM. In addition, a tumor necrosis factor (TNF) receptor was downregulated in both NICM and tions Supports and complements ongoing biomarker devel ICM, demonstrating the different signaling pathways opment efforts to differentiate heart failure of different involved in heart failure pathophysiology. These results offer etiologies (33). novel insight into unique disease-specific gene expression 0007 Over the past two decades, there have been remark that exists between end-stage cardiomyopathy of different able advances in medical and Surgical therapies designed to etiologies. This analysis demonstrates that transcriptome improve the symptoms and Survival of patients with heart analysis offers insight into pathogenesis-based therapies in failure, including angiotensin-converting enzyme (ACE) heart failure management, and complements studies using inhibitors, (62-64) beta-blockers, (65-58) aldosterone expression-based profiling to diagnose heart failure of dif antagonists, (69-70) angiotensin-receptor blockers, (71–73) ferent etiologies. US 2006/0246484 A1 Nov. 2, 2006 0012. The present invention provides a differential gene A2: LEPR, leptin receptor; LUM, lumican; MYH6, myosin expression profile, comprising comparative gene expression heavy chain 6: NAP1L3, nucleosome assembly protein levels resulting from gene expressions of a set of genes from 1-like 3: NPR3, atrionatriuretic peptide receptor C: patients having nonischemic cardiomyopathy compared to PHLDA1, pleckstrin homology-like domain family A mem gene expressions of a set of corresponding genes from ber 1: RPS4Y, ribosomal protein S4, Y-linked; S100A8, patients having nonfailing-hearts and a differential gene S100 calcium binding protein A8; SERPINE1, serine (or expression profile, comprising comparative gene expression cysteine) proteinase inhibitor, clade E, member 1: levels resulting from gene expressions of a set of genes from SLC39A8, solute carrier family 39, member 8: patients having ischemic cardiomyopathy compared to gene TNFRSF11B, tumor necrosis factor receptor superfamily expressions of a set of corresponding genes from patients
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