Atheroprotective Gene Therapy

动脉粥样硬化基因治疗

• 批准号: 10320358
• 负责人: David A Dichek
• 金额: $ 72.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320358
• 关键词: Achievement; Adenoviruses; Adipocytes; Animal Model; Animals; Anti-Inflammatory Agents; Apolipoprotein A-I; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biological Process; Blood Vessels; CMV promoter; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cells; Cessation of life; Cholesterol; Clinical; Coronary Artery Bypass; Critiques; DNA; DNA cassette; Data; Development; Disease; Elements; Endothelial Cells; Endothelium; Event; Funding; Future; Gene Transfer; Gene therapy trial; Genes; Genetic Engineering; Genetic Transcription; Genome; Goals; Growth; Helper-Inducer T-Lymphocyte; Hematological Disease; Hepatocyte; Human; Immunohistochemistry; Inflammation; Inflammatory; Interleukin-10; Intervention; LDL Cholesterol Lipoproteins; Laboratories; Lead; Lesion; Lipids; Liver; Low-Density Lipoproteins; Medical; Modeling; Morbidity - disease rate; Morphologic artifacts; Myocardial Infarction; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasma; Prevention; Proteins; Reproducibility; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Surgical Management; Testing; Time; Transcript; Transcriptional Regulation; Transgenes; United States; Vein graft; Veins; Western Blotting; Work; adenoviral-mediated; atheroprotective; base; cytokine; disability; gene therapy; gene transfer vector; gutless adenoviral vector; human mortality; improved; in silico; in vivo; inflammatory marker; insight; laser capture microdissection; limb loss; macrophage; member; mortality; nonhuman primate; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; preclinical study; prevent; promoter; rapid testing; reverse cholesterol transport; therapeutic gene; therapeutic transgene; therapy development; tool; transgene expression; vector

PROJECT SUMMARY Atherosclerosis is a disease of the blood vessel wall that causes heart attacks and strokes. Despite major advances in medical and surgical management, atherosclerosis still causes significant morbidity and mortality. For example, drug therapy that dramatically lowers LDL-cholesterol (to ~30 mg/dL) only marginally decreases adverse cardiovascular events and mortality. New approaches, beyond LDL lowering, are needed. The broad, long-term objective of this project is to develop a therapy that prevents and reverses atherosclerosis via interventions targeted at the blood vessel wall. This novel therapy involves the introduction and expression of disease-preventing genes in the cells that line blood vessel walls and is accordingly termed “atheroprotective gene therapy.” Blood vessels treated with this gene therapy would not develop atherosclerosis because they are genetically modified to resist the underlying biological processes that cause atherosclerosis: accumulation of cholesterol and inflammatory cells and activation of vascular cell inflammatory pathways. This project is focused on gene therapy that prevents cholesterol accumulation (and associated inflammation) in blood vessel walls. Vessel wall-targeted gene therapy is particularly well suited for prevention of atherosclerosis in veins used for coronary artery bypass grafts. Vein-graft atherosclerosis progresses rapidly, leads to graft narrowing and occlusion, and is inadequately treated. Our approach could eventually eliminate vein-graft atherosclerosis. 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 and take the next critical steps towards developing gene therapy that prevents and reverses atherosclerosis: Aim 1 will test whether HDAd-mediated expression of apolipoprotein A-I (apoA-I) or ATP-binding cassette subfamily A, member 1 (ABCA1) can prevent atherosclerosis in grafted rabbit veins. Aim 2 will develop novel expression cassettes that achieve high-level, stable, cell-specific transgene expression in endothelium in vivo. Aim 3 will identify the mechanisms through which atheroprotective gene therapy that produces apoA-I from endothelial cells prevents atherosclerosis. Accomplishment of the 3 aims will bring clinical vascular gene therapy closer to implementation by testing 2 promising therapeutic genes in a large animal model (Aim 1). Accomplishment of the aims may also yield novel vector platforms that are useful for expressing transgenes at high levels in endothelial cells and may also provide insights into mechanisms of endothelial cell gene transcription (Aim 2). Identification of the mechanisms through which apoA-I vascular gene therapy prevents atherosclerosis (Aim 3) will suggest approaches for improving apoA-I vascular gene therapy and for the development of adjunctive gene therapies.

项目摘要 动脉粥样硬化是一种血管壁疾病，会导致心脏病发作和中风。尽管主要 尽管内科和外科治疗取得了进展，但动脉粥样硬化仍然引起显著的发病率和死亡率。 例如，药物治疗，大大降低低密度脂蛋白胆固醇（~30毫克/分升），只有轻微减少 不良心血管事件和死亡率。除了降低LDL之外，还需要新的方法。那个女人 该项目的长期目标是开发一种通过以下途径预防和逆转动脉粥样硬化的疗法： 针对血管壁的干预。这种新的治疗方法包括引入和表达 血管壁细胞中的疾病预防基因，因此被称为“动脉粥样硬化保护基因 基因治疗”用这种基因疗法治疗的血管不会发展成动脉粥样硬化，因为它们 是基因改造，以抵抗潜在的生物过程，导致动脉粥样硬化：积累 胆固醇和炎性细胞以及血管细胞炎症通路的激活。这个项目是 专注于基因治疗，防止胆固醇积累（和相关的炎症）在血管 墙血管壁靶向基因治疗特别适用于预防静脉动脉粥样硬化 用于冠状动脉旁路移植术。静脉移植物动脉粥样硬化进展迅速，导致移植物狭窄 和闭塞，并且治疗不充分。我们的方法最终可以消除静脉移植物动脉粥样硬化。 有三个具体的目标，所有这些都是在兔子身上进行的。其目标是在临床上开发 有用的动脉粥样硬化保护基因治疗，通过有前途的基因转移载体，“辅助依赖性”， 腺病毒”（HDAd）。HDAd是一种有吸引力的人类基因治疗载体，因为它表达治疗性 在动物（包括非人类灵长类动物）中稳定多年的基因，并且相对非炎症性。的3 具体的目标是利用HDAd的前景，并采取下一步关键步骤，发展基因治疗 预防和逆转动脉粥样硬化：Aim 1将测试HDAd介导的 载脂蛋白A-I（apoA-I）或ATP结合盒亚家族A，成员1（ABCA 1）可以防止 移植兔静脉的动脉粥样硬化。目标2将开发新的表达盒， 在体内内皮中稳定的细胞特异性转基因表达。目标3将通过以下方式确定机制： 这种从内皮细胞产生apoA-I的动脉粥样硬化保护基因疗法预防动脉粥样硬化。 这3个目标的实现将使临床血管基因治疗更接近于实施， 在大型动物模型中有希望的治疗基因（Aim 1）。目标的实现也可能产生新的 载体平台可用于在内皮细胞中高水平表达转基因，并且还可以 提供了深入了解内皮细胞基因转录的机制（目的2）。识别 apoA-I血管基因治疗预防动脉粥样硬化的机制（Aim 3）将提示 改善apoA-I血管基因治疗和开发连续性基因治疗的方法。

项目成果

Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis.

• DOI: 10.1016/j.omtm.2023.08.018
• 发表时间: 2023-09-14
• 期刊: MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT
• 作者: Bi, Lianxiang;Wacker, Bradley K.;Komandur, Kaushik;Sanford, Nicole;Dichek, David A.
• 通讯作者: Dichek, David A.

A Rabbit Model for Testing Helper-Dependent Adenovirus-Mediated Gene Therapy for Vein Graft Atherosclerosis.

• DOI: 10.1016/j.omtm.2017.09.004
• 发表时间: 2017-12-15
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Bi L;Wacker BK;Bueren E;Ham E;Dronadula N;Dichek DA
• 通讯作者: Dichek DA

Novel expression cassettes for increasing apolipoprotein AI transgene expression in vascular endothelial cells.

• DOI: 10.1038/s41598-022-25333-9
• 发表时间: 2022-12-06
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Sethuraman, Meena;Dronadula, Nagadhara;Bi, Lianxiang;Wacker, Bradley K.;Knight, Ethan;De Bleser, Pieter;Dichek, David A.
• 通讯作者: Dichek, David A.