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(12) United States Patent (10) Patent No.: US 8,741,861 B2 Mann (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 8,741,861 B2 Mann (45) Date of Patent: Jun USOO8741861 B2 (12) United States Patent (10) Patent No.: US 8,741,861 B2 Mann (45) Date of Patent: Jun. 3, 2014 (54) METHODS OF NOVEL THERAPEUTIC McLaughlin et al. Pulmonary arterial hypertension, 2006, Circula CANDDATE DENTIFICATION THROUGH tion, 1.14:1417-1431).* GENE EXPRESSION ANALYSIS IN Vidal et al. Making sense of antisense, 2005, European Journal of VASCULAR-RELATED DISEASES Cancer, 41:2812-18.* Barst et al. Diagnosis and Differential Assessment of pulmonary (75) Inventor: David M. Mann, San Diego, CA (US) arterial hypertension, 2004, Journal of the American College of Car diology, vol.43, No. 12, Supplement S. p. 40S-47S.* (73) Assignee: Vascular Biosciences, San Diego, CA Esau et al., WO 2005/013901 A2, only pp. 1-250 are included.* (US) Chan and Loscalzo, “Pathogenic Mechanisms of Pulmonary Arterial Hypertension.” (2007) Journal of Molecular and Cellular Cardiology (*) Notice: Subject to any disclaimer, the term of this 44:14-30. patent is extended or adjusted under 35 Geracietal., “Gene Expression Patterns in the Lungs of Patients with U.S.C. 154(b) by 177 days. Primary Pulmonary Hypertension: A Gene Microarray Analysis.” (2001) Circulation Research 88:555-562. (21) Appl. No.: 12/934,950 Giaid and Saleh, “Reduced Expression of Endothelial Nitric Oxide Synthase in the Lungs of Patients with Pulmonary Hypertension.” (22) PCT Filed: Mar. 27, 2009 (1995) New England Journal of Medicine 333:214-221. Hoshikawa et al., “Hypoxia Induces Different Genes in the Lungs of (86). PCT No.: PCT/US2O09/038685 Rats Compared with Mice.” (2003) Physiological Genomics 12:209 219. S371 (c)(1), Kwapiszewska et al., “Expression Profiling of Laser-Microdissected (2), (4) Date: Dec. 21, 2010 Intrapulmonary Arteries in Hypoxia-Induced Pulmonary Hyperten sion.” (2005) Respiratory Research 6:109-124. (87) PCT Pub. No.: WO2009/121031 McMurtry et al., “Gene Therapy Targeting Survivin Selectively Induces Pulmonary Vascular Apoptosis and Reverse Pulmonary PCT Pub. Date: Oct. 1, 2009 Arterial Hypertension.” (2005) Journal of Clinical Investigation 115(6): 1479-1491. (65) Prior Publication Data Mittal et al., “Hypoxia-Dependent Regulation of Nonphagocytic US 2011 FOO91421 A1 Apr. 21, 2011 NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature.” (2007) Circulation Research 101:258-267. Motte et al., “Endothelin Receptor Antagonists.” (2006) Pharmacol Related U.S. Application Data ogy & Therapeutics 110:386-414. (60) Provisional application No. 61/040,065, filed on Mar. Ji et al., “MicroRNA Expression Signature and Antisense-Mediated 27, 2008. Depletion Reveal an Essential Role of MicroRNA Vascular Neointimal Lesion Formation.” (2007) Circulation Research (51) Int. Cl. 100: 1579-1588. CI2N IS/II (2006.01) Schermuly et al., “Phosphodiesterase 1 Upregulation in Pulmonary A6 IK38/00 Arterial Hypertension: Target for Reverse-Remodeling Therapy.” (2006.01) (2007) Circulation 115:2331-2339. GOIN I/00 (2006.01) Thistlethwaite et al., “Human angiopoietin gene expression is a (52) U.S. Cl. marker for severity of pulmonary hypertension in patients undergo CPC ........................................ G0IN I/00 (2013.01) ing pulmonary thromboendarterectomy.” J Thoracic Cardiovascular USPC ........................................ 514/44A: 514/15.7 Surgery (Jul. 2001) 122 (1):65-73. (58) Field of Classification Search None (Continued) See application file for complete search history. Primary Examiner — Tracy Vivlemore (56) References Cited Assistant Examiner — Kate Poliakova-Georgantas U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Lewis Kohn & Fitzwilliam LLP; David M. Kohn: Kari Moyer-Henry 5,406,959 A * 4, 1995 Mann ............................ 600,566 2005/OO37366 A1 2/2005 Gut et al. 2005, 0037946 A1 2/2005 Stagliano et al. 2006, OO19272 A1 1/2006 Geraci et al. (57) ABSTRACT 2006/0185027 A1* 8, 2006 Bartel et al. .................... 800/14 2007/0172856 A1 7/2007 Hogaboam et al. The present invention discloses multiple treatment regimens 2008/0171715 A1 7/2008 Brown et al. ................... 514,44 for vascular-related diseases and disorders. The present invention provides for methods of treating vascular-related FOREIGN PATENT DOCUMENTS disorders based on gene expression studies from Samples collected from individuals having symptoms of vascular-re WO WO 2008073922 A2 * 6, 2008 lated disorders. Additionally, methods are disclosed involv OTHER PUBLICATIONS ing diagnostic techniques to focus treatment regimens. Finally, methods of treating vascular-related disorder involv de la Torre, Is Alzheimer's disease a neurodegenerative or a vascular ing targeting microRNAS are also disclosed. disorder?, Mar. 2004, Lancet Neurology, vol. 3,3: 184-190.* Dictionary of Science and Technology, 1992, Academic Press, online edition. 11 Claims, 1 Drawing Sheet US 8,741,861 B2 Page 2 (56) References Cited plant rejection: diagnosis by pulmonary aterial biopsy.' Transplan tation (Apr. 2003) 75(7): 1-6. Fartoukh et al., “Chemokine macrophage inflammatory protein-1 OTHER PUBLICATIONS alpha mRNA expression in lung biopsy specimens of primary pull monary hypertension.” Chest (Jul. 1998) 114(1): 50S-51S. Rothman et al., “Increased expression of endoarterial vascular cell adhesion molecule-1 mRNA in an experimental model of lung trans- * cited by examiner U.S. Patent Jun. 3, 2014 US 8,741,861 B2 z?un61-I US 8,741,861 B2 1. 2 METHODS OF NOVEL THERAPEUTIC reversible (e.g. in newborns with congenital heart defects). In CANOIDATE DENTIFICATION THROUGH other patients, such as those with the idiopathic form, the GENE EXPRESSION ANALYSIS IN lesions are irreversible. It is unknown how these variations in VASCULAR-RELATED DISEASES PAH relate to one another on a molecular basis (Pearl et al 2002). CROSS-REFERENCES Current therapies for PAH patients primarily target vascu lar tone. Treatments that aim at correcting potassium channel This application claims the benefit of priority of U.S. Pro dysfunction (Machado et al 2001), nitric oxide impairment visional Application Ser. No. 61/040,065, filed on Mar. 27, (Humbert et al 2004), prostacyclin impairment (Tuder et al 2008, the disclosure of which is hereby incorporated by ref 10 1999, Christman et al 1992), and endothelin-1 expression erenced in its entirety. (Giaid etal 1993) have all been clinically available for several years. These therapies offer some relief from hemodynamic FIELD OF THE INVENTION symptoms, but most patients show only a transient response. The proliferative disease continues to progress in most PAH The present invention relates to assessment and identifica 15 patients, resulting in a five year mortality rate that remains at tion of expression of genes related to vascular-related dis around 50% (Newman et al 2004). eases. The present invention also includes methods of com Currently, there are no clinically available routine means to paring gene expression patterns with respect to various obtain endothelial and Smooth muscle samples from the pull disease states. monary arteries of pulmonary hypertension patients for diag nosis, disease staging or drug discovery. Applicant's earlier BACKGROUND OF THE INVENTION invention, described in U.S. Pat. No. 5,406,959, describes an endoarterial biopsy catheter that has demonstrated its safety Pulmonary arterial hypertension (PAH) is an occlusive dis and effectiveness in normal canines (Rothman, Mann et al., ease of the pulmonary arteries leading to serious hemody 1996), canines with experimentally-induced pulmonary namic abnormality, right heart failure, and premature death. 25 hypertension (Rothman, Mann et al., 1998), and canines with The molecular mechanisms behind PAH are still unclear. single-sided lung transplant rejection (Rothman, Mann et al., Without a more complete understanding of PAH and how its 2003). Preliminary studies have also demonstrated the safety complex vascular dysfunctions relate to one another, patients and efficacy of a catheter-based method to obtain endovascu will Suffer from imprecise diagnosis and drug therapy that lar samples from a porcine model of PAH. may be less than optimal. Despite recent advances and intro 30 Percutaneously-obtained pulmonary endoarterial biopsy duction of new clinically approved drugs, the 5-year Survival samples were found to be of Sufficient quantity and quality for from pulmonary hypertension remains an estimated 50% (Ar porcine whole genome mRNA microarray analysis and cher and Rich, 2000). Consequently, treatment for PAH, microRNA analysis. Whole genome microarray analysis while recently improved, still offers significant and long revealed time-sensitive variations in gene expression values lasting improvement in only a minority of patients. A meth 35 as PAH progressed in the Subject animal model. Genes pre odology to elucidate the molecular pathways associated with viously shown to be associated with PAH displayed changes PAH could guide the development of new therapies for this characteristic of the disease, and genes previously unassoci disease. ated with PAH also displayed expression level dysregulation. Though platelets and other cells may have a role in PAH, These findings raise the possibility that the endoarterial pulmonary endothelial cells and pulmonary Smooth muscle 40 biopsy catheter combined with microarray analysis may pro cells appear to be the primary sites of disease progression vide a valuable platform for the discovery of novel drug and (Humbert et al 2004). Molecular pathways that show abnor biomarker targets in pulmonary hypertension and a platform mality in pulmonary endothelial cells and
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