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Recent Angina News and Articles

• \"Micro-Rna Regulation in Ischemia and Ischemia-Reperfusion Injury\" in Patent Application Approval Process
• New Drug Discovery Study Findings Recently Were Reported by Researchers at Imperial College London
• Patent Issued for Tripyridyl Carboxamide Orexin Receptor Antagonists
• New Ischemia Study Findings Have Been Reported by Researchers at Wake Forest University
• Patent Issued for Delivery of a Sympatholytic Cardiovascular Agent to the Central Nervous System
• Researchers Submit Patent Application, \"Adhesive Patch Containing Bisoprolol\", for Approval
• Researchers Submit Patent Application, \"Apparatus and Methods for Anastomosis\", for Approval
• Studies from Wright State University School of Medicine Yield New Information about Blood Vessels
• University of Ioannina Details Research in Ezetimibe Therapy

"Method of Treating Myocardial Injury" in Patent Application Approval Process

Patent serial number 470769 is assigned to The Cleveland Clinic Foundation.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Adult stem cell based tissue repair is an emerging strategy for the treatment of ischemic tissue injury in multiple organ systems (Penn, M. S. and M. K. Khalil. 2008, Exploitation of stem cell homing for gene delivery. Expert. Opin. Biol. Ther. 8:17-30; Leri, A., J. Kajstura, P. Anversa, and W. H. Frishman. 2008. Myocardial regeneration and stem cell repair. Curr. Probl. Cardiol. 33:91-153; Dimmeler, S., J. Burchfield, and A. M. Zeiher. 2008. Cell-based therapy of myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 28:208-216). The majority of data to date suggest that the benefits in end organ function observed following stem cell administration are due to paracrine effects associated with the different factors released by the stem cells following engraftment. Rather, many of the benefits observed can be achieved through the injection of conditioned media in lieu of stem cell injection. These data have led some to conclude that adult stem cell engraftment and differentiation may not be necessary at all.

"Modulation of cardiac tissue repair after myocardial infarction (MI) can reduce ventricular remodeling (Zhang, M., N. Mal, M. kiedrowski, M. Chacko, A. T. Askari, Z. B. Popovic, O. N. Koc, and M. S. Penn. 2007. SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes following myocardial infarction. FASEB J. 21:3197-3207; Amado, L. C., A. P. Saliaris, K. H. Schuleri, J. M. St, J. S. Xie, S. Cattaneo, D. J. Durand, T. Fitton, J. Q. Kuang, G. Stewart, S. Lehrke, W. W. Baumgartner, B. J. Martin, A. W. Heldman, and J. M. Hare. 2005. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl. Acad. Sci. U.S. A 102:11474-11479; Urbanek, K., D. Torella, F. Sheikh, A. De Angelis, D. Nurzynska, F. Silvestri, C. A. Beltrami, R. Bussani, A. P. Beltrami, F. Quaini, R. Bolli, A. Leri, J. Kajstura, and P. Anversa. 2005. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc. Natl. Acad. Sci. U.S.A. 102:8692-8697). Stem cell transplantation represents a promising therapeutic alternative to help minimize myocardial loss and possibly regenerate lost cardiomyocyte cells after MI. The use of stem cells from embryonic, fetal and adult origins for cardiac tissue repair has been reported in experimental models of myocardial infarction (Urbanek, K., D. Torella, F. Sheikh, A. De Angelis, D. Nurzynska, F. Silvestri, C. A. Beltrami, R. Bussani, A. P. Beltrami, F. Quaini, R. Bolli, A. Leri, J. Kajstura, and P. Anversa. 2005. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc. Natl. Acad. Sci. U.S. A 102:8692-8697; Van't, H. W., N. Mal, Y. Huang, M. Zhang, Z. Popovic, F. Forudi, R. Deans, and M. S. Penn. 2007. Direct delivery of syngeneic and allogeneic large-scale expanded multipotent adult progenitor cells improves cardiac function after myocardial infarct. Cytotherapy 9:477-487; Murry, C. E., M. H. Soonpaa, H. Reinecke, H. Nakajima, H. O, Nakajima, M. Rubart, K. B. Pasumarthi, J. I. Virag, S. H. Bartelmez, V. Poppa, G. Bradford, J. D. Dowell, D. A. Williams, and L. J. Field. 2004. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664-668; Orlic, D., J. Kajstura, S. Chimenti, I. Jakoniuk, S. M. Anderson, B. Li, J. Pickel, R. McKay, B. Nadal-Ginard, D. M. Bodine, A. Leri, and P. Anversa. 2001. Bone marrow cells regenerate infarcted myocardium. Nature 410:701-705). Most of these studies describe the ability of stem cells to survive, engraft and to some extent improve heart function after transplantation. Nevertheless, the level of tissue recovery achieved by exogenous progenitors varies greatly depending on the source of stem cells (FASEB J. 21:3197-3207; Cytotherapy 9:477-487; Mooney, D. J. and H. Vandenburgh. 2008. Cell delivery mechanisms for tissue repair. Cell Stem Cell 2:205-213).

"In vitro stem cell differentiation on the other hand, often requires the stimulation with drugs, specific growth factors or cytokines that activate intracellular signaling driving the cells to a particular phenotype. Transforming growth factor beta family proteins (TGF.beta.1) have been shown to participate in cardiac development as well as cardiac myocyte differentiation in vitro (Mayorga M., Finan A., Penn M. Stem Cell Rev. 2009 Jan. 30. (Epub ahead of print); Lim, J. Y., W. H. Kim, J. Kim, and S. I. Park. 2007. Involvement of TGF.beta.1 signaling in cardiomyocyte differentiation from P19CL6 cells. Mol. Cells 24:431-436; Liu, Y., J. Song, W. Liu, Y. Wan, X. Chen, and C. Hu. 2003. Growth and differentiation of rat bone marrow stromal cells: does 5-azacytidine trigger their cardiomyogenic differentiation' Cardiovasc. Res. 58:460-468; Hahn, J. Y., H. J. Cho, H. J. Kang, T. S. Kim, M. H. Kim, J. H. Chung, J. W. Bae, B. H. Oh, Y. B. Park, and H. S. Kim. 2008. Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J. Am. Coll. Cardiol. 51:933-943; Li, T. S., T. Komota, M. Ohshima, S. L. Qin, M. Kubo, K. Ueda, and K. Hamano. 2008. TGF-beta induces the differentiation of bone marrow stem cells into immature cardiomyocytes. Biochem. Biophys. Res. Commun. 366:1074-1080; Faustino, R. S., A. Behfar, C. Perez-Terzic, and A. Terzic. 2008. Genomic chart guiding embryonic stem cell cardiopoiesis. Genome Biol. 9:R6). TGF.beta.1 in particular is known to control a variety of cellular processes such as cell proliferation, differentiation and apoptosis (Narine, K., W. O. De, V. D. Van, K. Francois, M. Bracke, S. DeSmet, M. Mareel, and N. G. Van. 2006. Growth factor modulation of fibroblast proliferation, differentiation, and invasion: implications for tissue valve engineering. Tissue Eng 12:2707-2716; Semlali, A., E. Jacques, S. Plante, S. Biardel, J. Milot, M. Laviolette, L. P. Boulet, and J. Chakir 2008. TGF-beta suppresses EGF-induced MAPK signaling and proliferation in asthmatic epithelial cells. Am. J Respir. Cell Mol. Biol. 38:202-208) and to regulate the production of extracellular matrix proteins in physiological and pathological conditions in different cell types. In addition, during the heart development TGF.beta.1 regulates the epithelial to mesenchymal transformation essential for heart valves and septum formation (Wang, X. J., Z. Dong, X. H. Thong, R. Z. Shi, S. H. Huang, Y. Lou, and Q. P. Li. 2008. Transforming growth factor-beta1 enhanced vascular endothelial growth factor synthesis in mesenchymal stem cells. Biochem. Biophys. Res. Commun. 365:548-554; Liu, F. Y., X. Z. Li, Y. M. Peng, H. Liu, and Y. H. Liu. 2008. Arkadia regulates TGF-beta signaling during renal tubular epithelial to mesenchymal cell transition. Kidney Int. 73:588-594).

"TGF.beta.1 activates a specific cell surface serine/threonine kinase receptor, TGF.beta.RI and II and the subsequent phosphorylation of Smad proteins that leads to the activation and nuclear translocation of transcription factors and regulation of transcriptional events (Prunier, C. and P. H. Howe. 2005. Disabled-2 (Dab2) is required for transforming growth factor beta-induced epithelial to mesenchymal transition (EMT). J Biol. Chem. 280:17540-17548; Brown, C. B., A. S. Boyer, R. B. Runyan, and J. V. Barnett. 1999. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 283:2080-2082). TGF.beta.1 might also activate other parallel signaling pathways implicating c-JUNactivated kinase or p38 MAPK (Hocevar, B. A., C. Prunier, and P. H. Howe. 2005. Disabled-2 (Dab2) mediates transforming growth factor beta (TGFbeta)-stimulated fibronectin synthesis through TGFbeta-activated kinase 1 and activation of the JNK pathway. J Biol. Chem. 280:25920-25927). Furthermore, it has been described that the TGF.beta.RI/II activated intracellular signaling may be regulated by a series of adaptor proteins such as disabled-2 (Dab2) (Jiang, Y., C. Prunier, and P. H. Howe. 2008. The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin. Oncogene 27:1865-1875; Derynck, R. and Y. E. Zhang. 2003. Smad-dependent and Smad-independent pathways in TGF-beta family signalling Nature 425:577-584) or Smad-anchor for receptor activation adaptor protein (SARA) (Shi, W., C. Chang, S, Nie, S. Xie, M. Wan, and X. Cao. 2007. Endofin acts as a Smad anchor for receptor activation in BMP signaling. J Cell Sci. 120:1216-1224; Runyan, C. E., H. W. Schnaper, and A. C. Poncelet. 2005. The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells. J Biol. Chem. 280:8300-8308). TGF.beta.1 treatment of epithelial cells leads to an up regulation of Dab2 critical for mesenchymal transformation."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent: "The present invention relates to a method of treating a myocardial injury of a subject. The method includes preparing a population of at least one of mesenchymal stem cells (MSCs), multipotent adult progenitor cells (MAPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), or any cell type of interest for myocardial regeneration. The population is treated with an agent that down-regulates expression of disabled-2 (Dab2) of the MSCs, MAPCs, ESCs, and iPSs of the population. The population is administered to a subject with the myocardial injury to treat the myocardial injury.

"In an aspect of the invention, the agent can comprise at least one of an RNAi agent that down regulates expression of Dab2, TGF.beta.1, or 5-azacytidine. The agent can be administered to the population at an amount effective to promote Wnt expression and/or activity from the MSCs, MAPCs, ESCs, and iPSs of the population. The agent can also be administered to the population at an amount effective to modulate the expression and/or activity of TGF.beta. adaptor proteins, such as SARA and Hgs/Hrs.

"In another aspect, the population can be treated prior to administration to the subject. The population can consist essentially of MSCs, MAPCs, ESCs, and iPSs and any other cell type of interest for myocardial regeneration. The population can be administered to injured myocardium by at least one of direct injection, venous infusion, and arterial infusion.

"In a further aspect, the myocardial injury can include at least one of arterial disease, atheroma, atherosclerosis, arteriosclerosis, coronary artery disease, arrhythmia, angina pectoris, congestive heart disease, ischemic cardiomyopathy, myocardial infarction, stroke, transient ischemic attack, aortic aneurysm, cardiopericarditis, infection, inflammation, valvular insufficiency, vascular clotting defects, and combinations thereof.

"The present invention also relates to a method of treating a myocardial infarction of a subject. The method includes preparing a population of at least one of mesenchymal stem cells (MSCs), multipotent adult progenitor cells (MAPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), or any cell type of interest for myocardial regeneration. The population is treated with an agent that down-regulates expression of disabled-2 (Dab2) of the MSCs, MAPCs, ESCs, and iPSs of the population. The population can be administered to infarcted myocardial tissue to treat the myocardial infarction.

"In an aspect of the invention, the agent can comprise at least one of an RNAi agent that down regulates expression of Dab2, TGF.beta.1, or 5-azacytidine. The agent can be administered to the population at an amount effective to promote Wnt expression and/or activity from the MSCs, MAPCs, ESCs, and iPSs of the population. The agent can also be administered to the population at an amount effective to modulate the expression and/or activity of TGF.beta. adaptor proteins, such as SARA and Hgs/Hrs.

"In another aspect, the population can be treated prior to administration to the subject. The population can consist essentially of MSCs, MAPCs, ESCs, and iPSs and any other cell type of interest for myocardial regeneration. The population can be administered to infarcted myocardium by at least one of direct injection, venous infusion, and arterial infusion.

"The present invention also relates to a method of treating ischemic cardiomyopathy of a subject. The method includes preparing a population of at least one of mesenchymal stem cells (MSCs), multipotent adult progenitor cells (MAPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), or any cell type of interest for myocardial regeneration. The population is treated with an agent that down-regulates expression of disabled-2 (Dab2) of the MSCs, MAPCs, ESCs, and iPSs of the population. The population can be administered to ischemic myocardial tissue to treat the ischemic cardiomyopathy.

"In an aspect of the invention, the agent can comprise at least one of an RNAi agent that down regulates expression of Dab2, TGF.beta.1, or 5-azacytidine. The agent can be administered to the population at an amount effective to promote Wnt expression and/or activity from the MSCs, MAPCs, ESCs, and iPSs of the population. The agent can also be administered to the population at an amount effective to modulate the expression and/or activity of TGF.beta. adaptor proteins, such as SARA and Hgs/Hrs.

"In another aspect, the population can be treated prior to administration to the subject. The population can consist essentially of MSCs, MAPCs, ESCs, and iPSs and any other cell type of interest for myocardial regeneration. The population can be administered to injured myocardium by at least one of direct injection, venous infusion, and arterial infusion."

URL and more information on this patent application, see: Penn, Marc S. Method of Treating Myocardial Injury. U.S. Patent Serial Number 470769, filed May 14, 2012, and posted January 10, 2013. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2898&p=58&f=G&l=50&d=PG01&S1=20130103.PD.&OS=PD/20130103&RS=PD/20130103

Keywords for this news article include: Kinase, Amino Acids, Muscle Cells, Cardiac Myocytes, Enzymes and Coenzymes, Transforming Growth Factors, TGF-beta Superfamily Proteins, The Cleveland Clinic Foundation, Intercellular Signaling Peptides and Proteins.

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