Bioreducible polymer-mediated gene therapy for the treatment of ischemic heart disease

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Title Bioreducible polymer-mediated gene therapy for the treatment of ischemic heart disease
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author McGinn, Arlo Nuttall
Date 2013-05
Description Coronary heart disease, especially myocardial infarction, is a serious and deadly disease that remains the number one cause of death in developed nations. While physicians have a wide array of drugs and tools at their disposal to treat myocardial infarction, there is a scarcity of drugs that effectively prevent the pathological remodeling of the left ventricle that occurs after acute infarction and greatly predisposes the patient to the risk of heart failure. This dissertation focuses on identifying nonviral, bioreducible polymer-based gene therapies to limit infarct expansion, prevent left ventricular remodeling, and retain heart function after myocardial infarction. Bioreducible polymers represent a major advancement in nonviral technology to transfect primary cells, with high efficiency, and low cytotoxicity. We first examined a combined gene/cell therapy-based strategy by implanting VEGF165-transfected primary skeletal myoblasts to the myocardium of infarcted rat hearts. The VEGF-expressing skeletal myoblasts acted as bioreactors, secreting proangiogenic VEGF and inducing new vessel formation in the infarcted hearts. This treatment strategy produced both global and regional improvements in the left ventricle, improving ejection fraction, decreasing cell death, and limiting left ventricular remodeling. A cationic polymer system utilizing arginine-grafted bioreducible polymer (ABP) was also used to efficiently mediate siRNA knockdown of BNIP3, a hypoxia-inducible iv proapoptotic protein. siRNA-mediated BNIP3 knockdown both in vitro and in vivo protected rat primary cardiomyocytes from hypoxic death. The inhibition of BNIP3 in acutely ischemic rat hearts resulted in improved retention of ejection fraction, decreased infarct formation, decreased cellular remodeling, and decreased left ventricular remodeling.
Type Text
Publisher University of Utah
Subject MESH Myocardial Infarction; Vascular Endothelial Growth Factor A; Polymers; Genetic Therapy; Ventricular Remodeling; Myoblasts, Skeletal; Angiogenesis Inducing Agents; Gene Knockdown Techniques
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Bioreducible Polymer-Mediated Gene Therapy for the Treatment of Ischemic Heart Disease. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © Arlo Nuttall McGinn 2013
Format application/pdf
Format Medium application/pdf
Format Extent 4,379,961 bytes
Source Original in Marriott Library Special Collections, RC39.5 2013.M34
ARK ark:/87278/s6f79mrp
Setname ir_etd
ID 196302
Reference URL https://collections.lib.utah.edu/ark:/87278/s6f79mrp
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