Adenovirus vectors and complement system

描述（由申请人提供）：正在进行的研究清楚地表明，静脉注射高剂量的基于腺病毒（Ad）的载体为治疗播散性癌症、遗传性疾病、血管疾病以及用于各种肝脏/遗传性疾病的肝脏基因治疗提供了巨大的潜力。然而，基于Ad的载体的全身施用目前被认为是高风险的策略，因为可能发生显著的急性毒性，包括趋化因子/细胞因子释放、内皮细胞损伤、枯否细胞活化、低血压、血小板减少症（低血小板计数），以及如在Gelsinger悲剧中所指出的全身炎症反应综合征和死亡。 关于通过以高剂量注射Ad载体立即触发的先天系统，人们知之甚少。这些系统的激活被预测在启动和/或调节随后的宿主免疫应答（先天性和适应性）中是关键的。这些第一线先天宿主防御系统之一是补体系统。不适当的补体激活可导致许多可怕的后果，包括过敏样反应、ARDS（成人呼吸窘迫综合征）、过度性休克、DIC（弥散性血管内凝血）、细胞因子释放和全身炎症反应综合征。更具体地，补体活化后释放的补体活化产物（即：C3 a、C5 a）是有效的炎症介质，已知其活化枯否细胞，以及活化血管内皮，导致中性粒细胞募集和血小板聚集。有趣的是，在高剂量Ad注射后也注意到许多这些后果。 基于这些考虑，我们提出了以下中心假设：“Ad载体与补体系统的相互作用导致通常归因于Ad载体使用的许多限制和毒性”。本提案的目的将直接检验中心假设。这一系列研究的结果将推动使用全身施用的Ad载体进行基因转移的领域向前发展。

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.