Adenovirus vectors and complement system

描述(申请人提供)：正在进行的研究表明，静脉注射大剂量的腺病毒(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/遗传性疾病的肝脏基因治疗提供了巨大的潜力。然而，全身性给药目前被认为是一种高风险的策略，因为可能会发生重大的急性毒性反应，包括趋化因子/细胞因子释放、内皮细胞损伤、库普弗细胞激活、低血压、血小板减少(低血小板计数)，以及盖尔辛格悲剧中所指出的全身炎症反应综合征和死亡。 关于高剂量注射Ad载体立即触发的固有系统，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反应中起关键作用，包括先天免疫反应和获得性免疫反应。补体系统是这些一线先天宿主防御系统之一。补体激活不当会导致一系列严重后果，包括过敏反应、ARDS(成人呼吸窘迫综合征)、低血压休克、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。更具体地说，补体激活后释放的补体激活产物(即C3a、C5a)是一种强有力的炎症介质，已知可以激活Kupffer细胞，也可以激活血管内皮细胞，导致中性粒细胞募集和血小板聚集。有趣的是，这些后果中的许多也是在大剂量Ad注射后被注意到的。 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了许多通常归因于使用Ad载体的局限性和毒性”。这项提议的目的将直接检验中心假说。这一系列研究的结果将推动使用系统管理的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.