Adenovirus vectors and complement system

腺病毒载体和补体系统

• 批准号: 7147257
• 负责人: Andrea na Amalfitano
• 金额: $ 15.49万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-05 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147257
• 关键词: Adenoviridae; Kupffer' s cell; complement; complement pathway regulation; enzyme linked immunosorbent assay; gene delivery system; immune response; immunocytochemistry; laboratory mouse; laboratory rat; neutrophil; platelet aggregation; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): Ongoing studies make it clear that the intravenous injection of high doses of Adenovirus (Ad) based vectors offer a tremendous potential for treatment of disseminated cancers, inherited diseases, vascular diseases, as well for gene therapy of the liver for a variety of hepatic/genetic diseases. However, the systemic administration of Ad based vectors is currently viewed as a highly risky maneuver, as significant acute toxicities can be incurred, including chemokine/cytokine release, endothelial cell damage, Kupffer cell activation, hypotension, thrombocytopenia (low platelet counts), and as noted in the Gelsinger tragedy, the systemic inflammatory response syndrome and death. Precious little is known about the innate systems that are immediately triggered by injection of an Ad vector at high doses. Activation of these systems is predicted to be pivotal in initiating and/or modulating subsequent host immune responses, both innate and adaptive. One of these first line innate host defense systems is the complement system. Inappropriate complement activation can result in a number of dire consequences, including anaphylactoid reactions, ARDS (adult respiratory distress syndrome), hypotensive shock, DIC (disseminated intravascular coagulation), cytokine release and systemic inflammatory response syndromes. More specifically, complement activation products released after complement activation (i.e: C3a, C5a) are potent inflammatory mediators, which are known to activate Kupffer cells, as well activate vascular endothelium, leading to neutrophil recruitment, and platelet aggregation. Intriguingly, many of these consequences are also noted after high dose Ad injections. Based upon these considerations, we forward the following Central Hypothesis: "Ad vector interactions with the complement system results in many of the limitations and toxicities typically attributed to the use of Ad vectors". The aims of this proposal will directly test the central hypothesis. The results of this line of investigation will move the field of gene transfer using systemically administered Ad vectors forward.

描述（由申请人提供）：正在进行的研究清楚地表明，静脉注射高剂量腺病毒（Ad）载体为治疗播散性癌症、遗传性疾病、血管疾病以及各种肝脏/遗传疾病的肝脏基因治疗提供了巨大的潜力。然而，基于Ad载体的全身给药目前被认为是一种高风险的操作，因为可能会产生显著的急性毒性，包括趋化因子/细胞因子释放、内皮细胞损伤、库普弗细胞活化、低血压、血小板减少（血小板计数低），以及如Gelsinger悲剧中所述的全身炎症反应综合征和死亡。