Polymer Carrier for Ischemia-Inducible Gene Therapy

用于缺血诱导基因治疗的聚合物载体

• 批准号: 7236587
• 负责人: DAVID ANDREW BULL
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236587
• 关键词: 3' Untranslated Regions; Acids; Address; Affect; American; Animals; Arterial Fatty Streak; Atomic Force Microscopy; Biological Assay; Chemicals; Chimeric Proteins; Cholesterol; Clinical; Complex; Condition; Congestive Heart Failure; Coronary artery; DNA; Development; Disease; Disease model; Drug Formulations; EPO gene; Elements; Enhancers; Erythropoietin; Gel; Gene Delivery; Gene Expression; Gene Targeting; Gene Transfer; Genes; Genetic Transcription; Goals; Hemangioma; Human; Hybrids; Hypoxia; In Vitro; Ischemia; Lead; Left Ventricular Function; Ligation; Luciferases; Methods; Modeling; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myocardium; Numbers; Oxygen; Oxygen measurement, partial pressure, arterial; Particle Size; Patients; Physical condensation; Polyethyleneimine; Polymers; Production; Proteins; Regulatory Element; Safety; Serum; Solubility; Staging; Surgical Models; Symptoms; System; Techniques; Testing; Therapeutic; Tissues; Titrations; Toxic effect; Transfection; Translations; VEGFA gene; Vascular Endothelial Growth Factors; Ventricular Function; Water; base; gene therapy; hypoxia inducible factor 1; improved; in vivo; mRNA Stability; mortality; novel; plasmid DNA; poly(ethylenimine)-co-(N-(2-aminoethyl) ethyleneimin)-co-N-(N-cholesteryloxycarbonyl-(2-aminoethyl)ethylenimine); promoter; protein degradation; protein expression; therapeutic gene; therapeutic protein; uptake; vector; water solubility

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：

项目成果

Cell penetrating peptide conjugated bioreducible polymer for siRNA delivery.

• DOI: 10.1016/j.biomaterials.2011.03.058
• 发表时间: 2011-08
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Nam, Hye Yeong;Kim, Jaesung;Kim, Soojin;Yockman, James W.;Kim, Sung Wan;Bull, David A.
• 通讯作者: Bull, David A.

Ligation of the left circumflex coronary artery with subsequent MRI and histopathology in rabbits.

• 发表时间: 2010-11
• 期刊: Journal of the American Association for Laboratory Animal Science : JAALAS
• 作者: N. Hu;C. Straub;Aida A Garzarelli;Kyle H Sabey;J. Yockman;D. Bull

Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis.

• DOI: 10.1016/j.biomaterials.2008.07.047
• 发表时间: 2008-11
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Kim, Sun Hwa;Jeong, Ji Hoon;Ou, Mei;Yockman, James W.;Kim, Sung Wan;Bull, David A.
• 通讯作者: Bull, David A.

Primary cardiomyocyte-targeted bioreducible polymer for efficient gene delivery to the myocardium.

• DOI: 10.1016/j.biomaterials.2010.07.025
• 发表时间: 2010-11
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Nam, Hye Y.;McGinn, Arlo;Kim, Pyung-Hwan;Kim, Sung W.;Bull, David A.
• 通讯作者: Bull, David A.