In vivo properties of gene transfer vectors and delivery in cardiovascular system

基因转移载体的体内特性和心血管系统中的递送

• 批准号: 6655320
• 负责人: THEODORE FRIEDMANN
• 金额: $ 27.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655320
• 关键词: Macaca nemestrina; atherosclerotic plaque; baboons; biotechnology; gene delivery system; laboratory mouse; low density lipoprotein; pharmacokinetics; transfection /expression vector

SPECIFIC AIMS: The hypothesis underlying all of these studies is that a full understanding of their pharmacokinetic and pharmacodynamic properties of gene transfer vectors will be required for the eventual development of tissue- and cell-specific vector targeting for precise and effective gene delivery. These studies are therefore intended to characterize the fate and effects of gene transfer into mice and a non- human primate and into the mouse and primate fetus and to characterize the host response to the genetic modification. The specific aims of the studies are: 1. to characterize the distribution and pharmacological properties, transgene expression and cellular effects of VSV-G-pseudotyped retrovirus and lentivirus vectors following systematic introduction into mice and macaques and into mouse and non-macaque fetuses. 2. to characterize mechanisms of initial vector interaction with cell surface receptors, with special attention to the role of primary attachment molecules such as glycosaminoglycans and selectins. 3. to determine the nature and extent of the host immune response to the vectors and their expressed transgenes; 4. to test the effects of in vivo expression of an antibody specific for the extra-cellular LDL of atherosclerotic lesions. 5. to characterize delivery of phage display peptide libraries to mouse and macaque fetuses and use in vivo phage panning methods to identify peptides that home to fetal tissues in vivo.

具体目标：所有这些研究的基础假设是，对基因转移载体的药代动力学和药效学特性的充分理解将是最终开发用于精确和有效基因递送的组织和细胞特异性载体靶向所必需的。因此，这些研究旨在表征基因转移至小鼠和非人灵长类动物以及小鼠和灵长类动物胎儿中的结局和影响，并表征宿主对遗传修饰的反应。本研究的具体目的是：1. 在系统性引入小鼠和猕猴以及小鼠和非猕猴胎儿后，表征VSV-G假型逆转录病毒和慢病毒载体的分布和药理学特性、转基因表达和细胞效应。2.表征初始载体与细胞表面受体相互作用的机制，特别注意初级附着分子如糖胺聚糖和选择素的作用。3.确定宿主对载体及其表达的转基因的免疫应答的性质和程度; 4.以测试对动脉粥样硬化病变的细胞外LDL特异性的抗体的体内表达的效果。5.以表征噬菌体展示肽文库向小鼠和猕猴胎儿的递送，并使用体内噬菌体淘选方法来鉴定体内归巢至胎儿组织的肽。