Hexon-modified adenovirus vectors

六邻体修饰的腺病毒载体

• 批准号: 7148543
• 负责人: Dmitry Shayakhmetov
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148543
• 关键词: Adenoviridae; blood; capsid; liver; liver cells; proteins; receptor; tissues; Adenoviridae; blood; capsid; liver; liver cells; proteins; receptor; tissues

DESCRIPTION (provided by applicant): Adenovirus vectors (Ad) are the second largest group of viral vectors extensively used in clinical trials in the US. The interest in Ad has recently expanded due to its potential as a vector for vaccination against anthrax and other life threatening infection agents. Despite significant knowledge regarding Ad interactions with cells in vitro, the molecular mechanisms governing infectivity, bio-distribution and toxicity of systemically applied Ad remain poorly understood. Numerous studies of Ad pharmacokinetics in vivo have shown that within the first few minutes after systemic application, more than 90% of the virus is cleared from the circulation by the liver, and that the liver is the predominant organ in the body transduced with Ad after systemic application. Our recent data suggest, however, that liver-mediated virus clearance occurs via two distinct molecular mechanisms. The first mechanism involves fiber-dependent receptor-mediated interactions of Ad with liver cells. The second mechanism, responsible for clearance of the bulk of systemically applied virus, does not depend on fiber-hepatic cell interactions. We hypothesized that hexon, the major Ad structural protein, is the main determinant mediating virus trapping in liver tissue independently of fiber-cellular receptor interactions. The overall goal of this study is to further our understanding of molecular mechanisms underlying liver-mediated Ad clearance from the blood, and to construct a safe capsid-modified vector, efficiently transducing target cells after systemic application at lower administered doses. The specific aims of the current proposal are: 1. To evaluate the role of Ad hexon in virus clearance from the blood using wild type Ads of different serotypes; 2. To develop Ad5-based vectors with mutated hexons and analyze their bio-distribution and persistence in circulation in a mouse model; and 3. To analyze efficacy of tumor cell targeting and systemic toxicity of hexon-mutated Ad5-based vectors upon their intravascular administration in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and may ultimately lead to the development of safe and efficient Ad vectors for the therapy of a wide range of inborn and acquired human diseases.

描述（由申请人提供）：腺病毒载体（AD）是美国广泛用于临床试验中的第二大病毒载体。由于其作为对炭疽和其他威胁生命的感染剂的疫苗接种的潜力，对AD的兴趣最近扩大了。尽管关于AD与细胞在体外的相互作用的知识很高，但具有感染性，生物分布和系统应用AD的毒性的分子机制仍然知之甚少。对体内AD药代动力学的大量研究表明，在全身应用后的前几分钟内，肝脏从循环中清除了90％以上的病毒，并且肝脏是全身应用后用AD转导的体内的主要器官。但是，我们最近的数据表明，肝介导的病毒清除率是通过两种不同的分子机制发生的。第一种机制涉及AD与肝细胞的纤维依赖性受体介导的相互作用。负责清除大部分系统应用病毒的第二种机制不取决于纤维热的细胞相互作用。我们假设主要的AD结构蛋白己酮是与纤维细胞受体相互作用无关的主要决定因素介导病毒捕获。这项研究的总体目标是进一步了解血液中肝介导的AD清除的分子机制，并构建安全的衣壳改性载体，在较低施用的剂量下进行全身应用后，有效地转导目标细胞。当前建议的具体目的是：1。使用不同血清型的野生型ADS评估AD Hexon在血液中从血液中清除的作用； 2。开发具有突变的六十六子的基于AD5的向量，并在小鼠模型中分析其生物分布和持续性；和3。分析小鼠模型中血管内给药的基于Hexon-Muthated Ad5的矢量的肿瘤细胞靶向和全身毒性的功效。 这些研究将极大地提高我们对体内AD-HOST相互作用的机制的理解，并最终可能导致开发安全有效的AD媒介，以治疗各种天生和获得的人类疾病。