Adenovirus-host interactions and in vivo virus targeting

描述（由申请人提供）：腺病毒是用于人类治疗应用的有前景的载体。Ad突变体的深刻表型之间的显着差异，在单个衣壳蛋白中具有修饰，并且我们在血管内病毒递送后不能选择性地靶向肿瘤细胞，这强调了当病毒通过血管内途径递送时，分子途径的冗余和重叠不受重视。该提议是进行全面的机制研究，以确定Ad衣壳的每个主要结构元件在体内介导病毒与肝细胞相互作用中的贡献。使用大量先前构建的衣壳修饰的Ad载体，我们将分析1）纤维结构; 2）五邻体-宿主整联蛋白相互作用;和3）六邻体-血液因子相互作用在介导Ad在肝脏中的捕获和血管内Ad递送后的肝细胞转导中的作用。基于积累的数据，我们将4）构建逃避肝脏捕获的肺癌细胞靶向溶瘤Ad载体，并在小鼠模型中评估其抗肿瘤功效。这些研究将极大地提高我们的了解的机制，在体内的广告主机相互作用，并最终导致临床上有用的靶向广告载体的发展，用于治疗局部和播散性转移性肿瘤疾病。 公共卫生相关性：腺病毒载体（Ad）是全球临床研究中最常见的病毒载体类型。尽管Ad广泛用于基因转移应用以及针对威胁生命的感染因子的疫苗接种，但由于对控制病毒感染性和体内生物分布的分子机制的理解不足，Ad作为抗癌治疗剂的用途受到极大阻碍。Ad肝细胞转导引起临床上显著的肝毒性，并使Ad靶向体内播散性转移性肿瘤细胞的策略复杂化。这个建议是为了填补我们在体内与宿主细胞和因子的相互作用的理解的主要空白。这些研究将最终导致开发出第一组临床上有用的靶向Ad载体，用于治疗局部和播散性转移性肿瘤疾病。

DESCRIPTION (provided by applicant): Adenoviruses are promising vectors for therapeutic applications in humans. The striking discrepancy between profound phenotypes of Ad mutants, possessing modifications in individual capsid proteins, and our inability to selectively target tumor cells after intravascular virus delivery underscores poorly appreciated redundancy and overlap of molecular pathways, which become engaged when virus is delivered via intravascular route. This proposal is to conduct comprehensive mechanistic studies to define the contribution of each of the major structural elements of the Ad capsid in mediating virus interaction with liver cells in vivo. Using a large set of previously constructed capsid- modified Ad vectors, we will analyze the role of 1) the fiber structure; 2) the penton-host integrin interactions; and 3) the hexon-blood factor interactions in mediating Ad trapping in the liver and hepatocyte transduction after intravascular Ad delivery. Based on the accumulated data we will 4) construct a lung carcinoma cell-targeted oncolytic Ad vector that escapes trapping by the liver and evaluate its anti-tumor efficacy in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and will ultimately lead to the development of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases. PUBLIC HEALTH RELEVANCE: Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Despite extensive use in gene transfer applications as well as vaccinations against life threatening infectious agents, Ad's use as an anti-cancer therapeutic is greatly impeded due to poor understanding of the molecular mechanisms that govern virus infectivity and bio-distribution in vivo. Ad liver cell transduction causes clinically significant hepatotoxicity and complicates strategies for Ad targeting to disseminated metastatic tumor cells in vivo. This proposal is to fill the major void in our understanding of Ad interactions with host cells and factors in vivo. These studies will ultimately lead to the development of a first panel of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.