Despite advances in the treatment of ischemic heart disease (IHD), more than 500,000 Americans progress to end-stage IHD and congestive heart failure each year. Gene therapy has emerged as a promising option for the treatment of IHD. Gene therapy using Vascular Endothelial Growth Factor (VEGF) has recently been demonstrated to help preserve myocardial function following coronary artery ligation in animals and to help relieve symptoms of myocardial ischemia in initial human trials. Significant limitations remain, however, to the broad applicability of gene therapy. Current methods of gene delivery to the myocardium are limited by the potential for patient morbidity and mortality or, alternatively, by low transfection efficiency. Further, gene therapy for IHD that affects both ischemic and non-ischemic myocardium is associated with angioma formation and atherosclerotic plaque progression. Before gene therapy can be widely applied to IHD, techniques for safe, efficient gene transfection and regulated gene expression will need to be developed. We propose to: 1) develop two novel multifunctional cationic water-soluble lipopolymers to achieve high levels of targeted gene transfection with minimal toxicity and 2) develop therapeutic gene constructs for IHD whose expression is regulated by oxygen tension within the myocardium. Our lipopolymers contain a cationic DNA condensing agent, a hydrophilic spacer, and a hydrophobic molecule. These polymers offer good solubility, effective lysosomal escape and efficient uptake. The erythropoietin EPO enhancer, the EPO 3'- untranslated region (3'-UTR) and an oxygen dependent degradation domain will be incorporated into the VEGF gene to promote stable protein expression in only ischemic regions of the myocardium. These gene constructs will be delivered to the myocardium using water-soluble lipopolymer carriers. After demonstrating high transfection efficiency and ischemia-inducible gene expression in vitro, we will test the regulated expression of VEGF in vivo in surgical models of IHD. These studies will be integral to the development of 1) a clinically useful vector for efficient transfection of the myocardium with minimal toxicity and 2) therapeutic genes whose expression is limited to ischemic regions of the myocardium, helping to make the safe application of gene therapy for IHD a clinical reality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071541-02
Application #
6765120
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Dunn, Rosalie
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$373,750
Indirect Cost
Name
University of Utah
Department
Surgery
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Won, Young-Wook; Lee, Minhyung; Kim, Hyun Ah et al. (2012) Post-translational regulated and hypoxia-responsible VEGF plasmid for efficient secretion. J Control Release 160:525-31
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Nam, Hye Yeong; Nam, Kihoon; Lee, Minhyung et al. (2012) Dendrimer type bio-reducible polymer for efficient gene delivery. J Control Release 160:592-600
Nam, Hye Yeong; Kim, Jaesung; Kim, Sung Wan et al. (2012) Cell targeting peptide conjugation to siRNA polyplexes for effective gene silencing in cardiomyocytes. Mol Pharm 9:1302-9
McGinn, Arlo N; Nam, Hye Yeong; Ou, Mei et al. (2011) Bioreducible polymer-transfected skeletal myoblasts for VEGF delivery to acutely ischemic myocardium. Biomaterials 32:942-9
Nam, Hye Yeong; Kim, Jaesung; Kim, Soojin et al. (2011) Cell penetrating peptide conjugated bioreducible polymer for siRNA delivery. Biomaterials 32:5213-22
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Ou, Mei; Kim, Tae-il; Yockman, James W et al. (2010) Polymer transfected primary myoblasts mediated efficient gene expression and angiogenic proliferation. J Control Release 142:61-9

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