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Atheroprotective Gene Therapy

动脉粥样硬化基因治疗

基本信息

批准号：
9023584
负责人：
David A Dichek
金额：
$ 51.15万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-10 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9023584
关键词：
Achievement Address Adenoviruses American Animal Model Animals Apolipoprotein A-I Arterial Fatty Streak Arteries Atherosclerosis Biological Process Blood Circulation Blood Vessels Bypass CMV promoter Cardiovascular Diseases Carotid Arteries Cause of Death Cell Adhesion Molecules Cell Line Cells Cessation of life Cholesterol Chronic Disease Clinical Clinical Medicine Clinical Trials Coronary Circulation DNA cassette Data Deposition Development Diabetes Mellitus Disease Endothelial Cells Endothelin-1 Endothelium Enhancers Epidemic Experimental Animal Model Fatty acid glycerol esters Future Gene Transfer Gene therapy trial Genes Genetic Engineering Goals Growth Health Human In Situ Inflammation Infusion procedures Interleukin-10 Laboratories Lesion Life Limb structure Lipids Medical Messenger RNA Methods Modeling Morbidity - disease rate Mus Myocardial Infarction Obesity Oryctolagus cuniculus Pattern Principal Investigator Protocols documentation Research Stroke Structure of jugular vein Surgical Management Testing Therapeutic Agents Therapeutic Studies Toxic effect United States Vascular Diseases Vascular Endothelial Cell Vein graft Veins Venous Work aging population atheroprotective base cellular transduction clinical application clinically relevant disability feeding gene therapy gene transfer vector human disease human mortality implantation improved in vivo macrophage mortality new growth nonhuman primate novel novel therapeutics pre-clinical prevent programs promoter research study success therapeutic gene therapeutic transgene transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a disease of the blood vessel wall that causes heart attacks, strokes, and loss of limbs. Despite major advances in medical and surgical management, atherosclerosis still causes significant morbidity and mortality. The impact of atherosclerosis on the health of the American people is expected to increase in the coming decades due to aging of the population and the consequences of the current obesity/diabetes epidemic. The broad, long-term objective of this project is to develop a novel therapy that decreases the morbidity and mortality of atherosclerosis. This novel therapy involves the introduction and expression of disease-preventing genes in the cells that line the blood vessel wall, and is appropriately termed "atheroprotective gene therapy". Blood vessels treated with atheroprotective gene therapy would not develop atherosclerosis because they have been genetically modified to resist the underlying biological processes that cause atherosclerosis, including inflammation and accumulation of fat deposits in the blood vessel wall. There are 3 specific aims, all of which are carried out in rabbits. The aims are focused on developing clinically useful atheroprotective gene therapy, delivered by a promising gene-transfer vector, "helper-dependent adenovirus" (HDAd). HDAd is an attractive vector for human gene therapy because it expresses therapeutic genes stably for years in animals (including nonhuman primates) and is relatively non-inflammatory. The 3 specific aims exploit the promise of HDAd to address critical issues in preclinical gene-therapy research: 1) demonstration of long-term efficacy and lack of toxicity in large animal models of human disease (Aims 1 and 3); and 2) achievement of transgene expression levels that are sufficiently high to treat and prevent chronic diseases while minimizing the need for infusion of large amount of vectors (Aim 2). The first specific aim uses 2 animal models of robust atherosclerotic lesion growth and a model of atherosclerosis regression to test whether expression of apolipoprotein A-I in arterial endothelial cells can prevent growth of new atherosclerotic lesions and promote regression of existing lesions. The second specific aim develops improved expression cassettes that allow HDAd to express therapeutic genes at higher, more stable levels, specifically in endothelial cells. The third specific aim tests whether HDAd can achieve persistent expression of an atheroprotective gene in the clinically relevant setting of venous bypass grafting. Accomplishment of these 3 aims will bring clinical vascular gene therapy closer to implementation. Moreover, achievement of the aims will establish new experimental animal models and novel vector platforms for expressing therapeutic genes. These new models and vectors will facilitate development-both by our laboratory and others-of gene-based therapies that prevent and reverse human vascular disease.

描述（由申请人提供）：动脉粥样硬化是一种血管壁疾病，可导致心脏病发作、中风和肢体丧失。尽管在医疗和外科治疗方面取得了重大进展，动脉粥样硬化仍然导致显著的发病率和死亡率。由于人口老龄化和当前肥胖/糖尿病流行的后果，动脉粥样硬化对美国人健康的影响预计将在未来几十年增加。该项目的长期目标是开发一种新的治疗方法，降低动脉粥样硬化的发病率和死亡率。这种新疗法涉及在血管壁细胞中引入和表达预防疾病的基因，并被恰当地称为“动脉粥样硬化保护基因疗法”。用动脉粥样硬化保护基因疗法治疗的血管不会发展成动脉粥样硬化，因为它们经过基因修饰，可以抵抗导致动脉粥样硬化的潜在生物过程，包括炎症和血管壁脂肪沉积的积累。有3个具体的目标，都是在兔子身上实现的。目的是开发临床有用的动脉粥样硬化保护基因治疗，通过一种有前途的基因转移载体，“辅助依赖腺病毒”（HDAd）。HDAd是一种有吸引力的人类基因治疗载体，因为它在动物（包括非人类灵长类动物）中稳定表达治疗基因多年，并且相对无炎症。三个具体目标利用HDAd的前景来解决临床前基因治疗研究中的关键问题：1)在人类疾病的大型动物模型中证明长期疗效和缺乏毒性（目标1和3）；2)实现足够高的转基因表达水平，以治疗和预防慢性疾病，同时最大限度地减少对大量载体输注的需求（目标2）。第一个具体目的是使用2个动脉粥样硬化病变生长健壮的动物模型和一个动脉粥样硬化回归模型来测试载脂蛋白a - i在动脉内皮中的表达