Adenovirus-host interactions and in vivo virus targeting

腺病毒-宿主相互作用和体内病毒靶向

• 批准号: 7736713
• 负责人: Dmitry Shayakhmetov
• 金额: $ 54.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736713
• 关键词: Ablation; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Affect; Affinity; Amino Acid Sequence; Amino Acids; Area; Binding; Binding Sites; Biology; Blood; Blood Circulation; Blood Coagulation Factor; Blood Platelets; Capsid; Capsid Proteins; Cell Communication; Cell surface; Cells; Classification; Clinical Research; Clinical Trials; Coagulation Process; Collaborations; Complex; Cryoelectron Microscopy; DNA; Data; Deposition; Development; Discontinuous Capillary; Disease; Dose; Elements; Employee Strikes; Endosomes; Endothelial Cells; Factor Analysis; Factor IX; Fiber; Gene Delivery; Gene Transfer; Generations; Goals; Hepatocyte; Hepatotoxicity; Histocompatibility Testing; Human; Human Adenoviruses; Human Genetics; Immune response; In Vitro; Individual; Infection; Infectious Agent; Inflammatory; Integrins; Intravenous; Investigation; Knowledge; Kupffer Cells; Lead; Life; Liver; Local Therapy; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Minor; Modeling; Modification; Molecular; Mutate; Mutation; Neoplasm Metastasis; Oncolytic; Pathway interactions; Peptides; Phenotype; Protein Binding; Proteins; RGD (sequence); Research; Resolution; Risk; Role; Route; Safety; Saturn' s Moon Phoebe; Series; Serotyping; Structure; Surface Plasmon Resonance; Therapeutic; Therapeutic Intervention; Tissues; Tropism; Universities; Vaccination; Variant; Viral; Viral Vector; Virus; Virus Diseases; adenovirus penton protein; adenovirus receptor; anti-cancer therapeutic; base; cell type; cellular transduction; clinical application; clinically significant; defined contribution; flexibility; gene delivery system; improved; in vivo; lung Carcinoma; monocyte; mouse model; mutant; neoplastic cell; novel; particle; penton base; prevent; public health relevance; therapeutic gene; transgene expression; tumor; tumor-selective adenovirus; vector; virus host interaction

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.

描述(申请人提供)：腺病毒是人类治疗应用的很有前途的载体。深刻的Ad突变体表型之间的显著差异，具有个别衣壳蛋白的修饰，以及我们在血管内病毒输送后无法选择性地靶向肿瘤细胞之间的显著差异，突显了当病毒通过血管内途径输送时，分子通路的冗余和重叠。这项建议是为了进行全面的机制研究，以确定在体内介导病毒与肝细胞相互作用的每个主要结构元件的作用。利用一大组先前构建的衣壳修饰的Ad载体，我们将分析1)纤维结构；2)五色子-宿主整合素相互作用；以及3)六邻体-血液因子相互作用在介导Ad在血管内传递后在肝脏中的捕获和肝细胞转导中的作用。基于积累的数据，我们将4)构建能够逃脱肝脏捕获的肺癌细胞靶向性溶瘤重组腺病毒载体，并在小鼠模型中评价其抗肿瘤效果。这些研究将极大地提高我们对体内Ad-宿主相互作用机制的理解，并最终将导致临床上有用的靶向Ad载体的开发，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)是全世界临床研究中最常见的病毒载体类型。尽管它被广泛应用于基因转移和疫苗接种，但由于缺乏对控制病毒感染性和体内生物分布的分子机制的了解，其作为抗癌治疗药物的应用受到了极大的阻碍。Ad肝细胞转导在临床上会引起明显的肝毒性，并使Ad靶向体内播散性转移肿瘤细胞的策略复杂化。这一建议是为了填补我们在体内对Ad与宿主细胞和因子相互作用的了解的主要空白。这些研究最终将导致开发第一批临床有用的靶向Ad载体，用于治疗局部和播散性转移性肿瘤疾病。