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(12) United States Patent (10) Patent No.: US 8,722,625 B2 Culiat (45) Date of Patent: May 13, 2014

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(12) United States Patent (10) Patent No.: US 8,722,625 B2 Culiat (45) Date of Patent: May 13, 2014 USOO8722625B2 (12) United States Patent (10) Patent No.: US 8,722,625 B2 Culiat (45) Date of Patent: May 13, 2014 (54) TREATMENT OF CARDIOVASCULAR Zhang, X. et al., “Nell-1 induces acrania-like cranioskeletal deformi DSORDERS USING THE CELL ties during mouse embryonic development'. Lab Invest 86(7): 633 644 (2006). DIFFERENTATION SIGNALNG PROTEIN Zhang, X. et al., “Overexpression of Nell-1, a craniosynostosis NELL1 associated gene, induces apoptosis in osteoblasts during craniofacial development”, J Bone Miner Res. 18(12): 2126-2134 (2003). (75) Inventor: Cymbeline T. Culiat, Oak Ridge, TN Ting, K. et al., “Human NELL-1 expressed in unilateral coronal (US) synostosis”, J Bone Miner Res. 14(1): 80-90 (1999). Aghaloo, T. et al., “Nell-1-induced bone regeneration in calvarial defects”, Am J Pathol. 169(3):903-915 (2006). (73) Assignee. UT-Battelle, LLC, Oak Ridge, TN (US) Zhang, X. et al., “Craniosynostosis in transgenic mice overexpress ing Nell-1 "...J Clin Invest. 110(6): 861-870 (2002). (*) Notice: Subject to any disclaimer, the term of this Cowan, C.M. et al., “Nell-1 induced bone formation within the dis patent is extended or adjusted under 35 tracted intermaxillary Suture', Bone 38(1): 48-58 (2006). U.S.C. 154(b) by 877 days. Desai, J. et al., “Nell-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects'. (21) Appl. No.: 12/284,667 Hum Mol Genet. 15(8): 1329-1341 (2006). Maeda, K. et al., “Brain specific human genes, NELL1 and NELL2, (22) Filed: Sep. 24, 2008 are predominantly expressed in neuroblastoma and other embryonal neuroepithelial tumors”, Neurol Med Chir (Tokyo) 41(12): 582-588 (65) Prior Publication Data (2001). Luce, M. J. et al., “The neuronal EGF-related genes NELL1 and US 2009/OO87415A1 Apr. 2, 2009 NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage'. Gene 231(1-2): 121-126 (1999). Kuroda, S. et al., “Biochemical characterization and expression Related U.S. Application Data analysis of neural thrombospondin-1-like roteins Nell and NELL2”. (60) Provisional application No. 60/995,854, filed on Sep. Biochem Biophy's Res Commun. 265(1): 79-86 (1999). 28, 2007, provisional application No. 61/079,446, Watanabe, T.K. et al., “Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six filed on Jul. 10, 2008. EGF-like repeats”. Genomics 38:273-276 (1996). Shen, Y. et al., “Knock Down of NELL2 in Wilms' Tumor Cell Line', (51) Int. Cl. Journal of the William Jarvie Society, vol. 49, p. 4.1(2006), Abstract. A6K38/00 (2006.01) Santini, M. P. et al., “Signalling pathways in cardiac regeneration'. A6 IK38/02 (2006.01) Novartis Found Symp. 274: 228-238 (2006). A6 IK 4.8/00 (2006.01) Rubart, M. et al., “Cell-based approaches for cardiac repair'. Ann NY (52) U.S. Cl. AcadSci, 1080: 34-38 (2006). USPC .......................... 514/16.4: 514/44 R: 514/1.1 Ott, H. C. et al., “From cardiac repair to cardiac regeneration—ready to translate?”, Expert Opin Biol Ther: 6(9): 867-878 (2006). (58) Field of Classification Search Rosenthal, N. et al., “Growth factor enhancement of cardiac regen USPC ........................................ 514/16.4, 1.1, 44 R eration”. Cell Transplant I5(Suppl I): S41-S45(2006). See application file for complete search history. Kuroda, S. et al., “Involvement of epidermal growth factor-like domain of NELL proteins in the novel protein-protein interaction (56) References Cited with protein kinase C.”. Biochem Biophy's Res Commun. 265(3): 752-757 (1999). U.S. PATENT DOCUMENTS Haider, H. K.H., “Bone marrow cells for cardiac regeneration and repair: current status and issues'. Expert Rev Cardiovasc Ther: 4(4): 7,052,856 B2 5/2006 Ting 7,910,542 B2 3/2011 Culiat 557-568 (2006). 2004/0186423 A1 9, 2004 Cafferata Orlic, D. et al., “Transplanted Adult Bone Marrow Cells Repair 2006.0025367 A1 2/2006 Simari Myocardial Infarcts in Mice'. Ann N Y Acad Sci 938(1):221 2006.0053503 A1 3, 2006 Culiat et al. 230(2001). 2006/011 1313 A1 5/2006 Ting et al. Lu, S.S. et al., “The osteoinductive properties of Nell-1 in a rat spinal 2006/0228392 A1 10/2006 Ting fusion model”, The Spine Journal 7(1): 50-60 (2007). 2006, O292670 A1 12/2006 Ting et al. The Reporter, No. 78 (Jun. 2006), published by Oak Ridge National 2007/0134291 A1 6/2007 Ting et al. Laboratory, accessible on line at http://www.ornil.gov/info/reporter? 2009, O142312 A1 6, 2009 Culiat no78 une06 dw.htm. 2011/0236325 A1 9, 2011 Culiat et al. (Continued) FOREIGN PATENT DOCUMENTS Primary Examiner — Taeyoon Kim WO 02/100.426 A1 12/2002 (74) Attorney, Agent, or Firm — Edna I. Gergel WO 2004/072100 A1 8, 2004 WO 2009/042859 A1 4/2009 WO 2011091244 T 2011 (57) ABSTRACT It has been identified in accordance with the present invention OTHER PUBLICATIONS that Nell 1 is essential for normal cardiovascular development Liu, L. et al., “Characterizing the Role of the Nell Gene in Cardio by promoting properformation of the heart and blood vessels. vascular Development'. Office of Workforce Development for Teach The present invention therefore provides therapeutic methods ers and Scientist, (2007), Abstract. for treating cardiovascular disorders by employing a Nell Tsutsumi, S. et al., “The Novel Gene Encoding a Putative protein or nucleic acid molecule. Transmembrane Protein is Mutated in Gnathodiaphyseal Dysplasia (GDD), Am. J. Hum. Genet 74: 1255-1261 (2004). 14 Claims, 6 Drawing Sheets US 8,722.625 B2 Page 2 (56) References Cited Lee, M. etal. “Effect of Nell-1 Deliveryon Chondrocyte Proliferation and Cartilaginous Exracellular Matrix Deposition' Tissue Eng. Part OTHER PUBLICATIONS A (2010) pp. 1791-1800, vol. 16, No. 5. Abstract entitled “Characterizing the Role of the Nell Gene in Liu, L. et al., “Characterizing the Role of the Nell 1 Gene in Cardio Cardiovascular Development” from the 2007 American Association vascular Development” Oak Ridge Science Semester Poster Presen for the Advancement of Science (AAAS) Annual Meeting entitled tation, ORNL, Oak Ridge, TN. Presentation on Aug. 11, 2006 "Science and Technology for Sustainable Well-Being” that occurred (Poster). on Feb. 15-19, 2007, pp. A125. Rinchik, E.M. et al., “Functional Annotation of Mammalian Aghaloo.T. et al., “A Study of the Role of Nell-1 Gene Modified Goat Genomic DNA Sequence by Chemical Mutagenesis: A Fine-Struc Bone Marrow Stromal Cells in Promoting New Bone Formation” ture Genetic Mutation Map of a 1-to 2-cMSegment of Mouse Chro Molecular Therapy (2007) pp. 1872-1880, vol. 15, No. 10. mosome 7 Corresponding to Human Chromosome 1 lp14p15” PNAS Bareggi. R. et al., “Protein Kinase C (PKC) Isoenzymes Exhibit (2002) pp. 844-849, vol. 99, No. 2. Specific Expression in the Vertebral Column of Human Fetuses” Chen, W. et al., “Nfatc2 is a Primary Response Gene of Nell-1 Journal of Biological Reseasrch (1995) pp. 83-91, vol. LXXI. Regulating Chondrogenesis in ATDC5 Cells' Journal of Bone and Cowan, et al., “Synergistic Effects of Nell-1 and BMP-2 on the Mineral Research (2011) pp. 1230-1241, vol. 26, No. 6. Osteogenic Differentiation of Myoblasts,” Journal of Bone Mineral Liu et al., “Characterizing the Role of the Nell Gene in Cardiovas Reseasrch (2007) pp. 918-930, vol. 22. cular Development.” U.S. Department of Energy Journal of Under Culiat, C.T. et al., “Nell 1: A Candidate Gene for ENU-Induced graduate Research, 2007, pp. 63-70. Recessive Lethal Mutations at the 17R6 Locus and Potential Mouse Franke et al., “Systematic Association Mapping Identifies NELL1 as Models for Human Neonatal Unilateral . .” International Mamma a Novel IBD Disease Gene.” PLoS One, 2007, pp. 1-13, vol. 8(e691) lian Genome Society, 15th International Mouse Genome Conference and Supplemental documents. (2001). Culiat et al., “Nell 1: A Candidate Gene for ENU-Induced Recessive Desai, J. et al., “Nell1. A Gene Coding for a Novel PKC-Binding Lethal Mutations at the 17R6 Locus and Potential Mouse Models for Protein Isa Candidate for Late-Gestation Recessive Lethal Mutations Human Neonatal Unilateral Coronal Synostosis (UCS).” Jan. 27-31. at the I7R6 Locus' 16th International Mouse Genome Conference, 2002 (Abstract). San Antonio, TX. Presentation on Nov. 17-21, 2002 (Abstract). Desai et al., “Nelll-Deficient Mice Have Reduced Expression of Desai, J. et al., “Characterization of Mouse Nell 1: A Gene Coding for Extracellular Matrix Proteins Causing Cranial and Vertebral a Novel PKC-Binding Protein' Women in Science Meeting, ORNL. Defects.” 20th International Mouse Genome Conference, Charles Oak Ridge, TN. Presentation on May 1, 2006 (Abstract). ton, SC, Presentation on Nov. 14, 2006 (Abstract). U.S. Patent May 13, 2014 Sheet 1 of 6 US 8,722,625 B2 U.S. Patent May 13, 2014 Sheet 2 of 6 US 8,722,625 B2 *::: 838-38 U.S. Patent May 13, 2014 Sheet 3 of 6 US 8,722.625 B2 Figure 4A-4C U.S. Patent May 13, 2014 Sheet 5 of 6 US 8,722,625 B2 U.S. Patent May 13, 2014 Sheet 6 of 6 US 8,722,625 B2 igaret A-7. US 8,722,625 B2 1. 2 TREATMENT OF CARDOVASCULAR order is prevented or is delayed; or alternatively, its progres DSORDERS USING THE CELL sion is slowed down, the extent of the injury is reduced, and DIFFERENTATION SIGNALING PROTEIN the recovery is accelerated. NELL1 In one embodiment, the present invention provides a method of treating a cardiovascular disorder by administering CROSS REFERENCE TO RELATED a Nell1 protein or functional derivatives thereof to a subject in APPLICATIONS need of the treatment.
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