Adenovirus interaction with platelets

腺病毒与血小板的相互作用

基本信息

批准号：
7895536
负责人：
ANDRE Michael LIEBER
金额：
$ 19.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895536
关键词：
Adenovirus Vector Adenoviruses Affect Amino Acids Animals Antibodies Binding Biodistribution Blood Platelets Blood Vessels CD46 Antigen Capsid Capsid Proteins Cells Charge Communicable Diseases Data Fiber Gene Transfer Goals Hepatocyte Human In Vitro Infection Injection of therapeutic agent Insecta Intravenous Kupffer Cells Libraries Liver Mediating Metastatic Neoplasm to the Liver Modification Mus Mutation Neoplasm Metastasis Oncolytic Outcome Study Pathway interactions Pattern Platelet aggregation Prevalence Proteins Recombinant Proteins Recombinants Refractory Role Safety Serotyping Serum Stem cells System Testing Tissues Tropism Vaccination Variant Viral Vector Virus base blood treatment gene therapy improved in vivo intravenous administration intravenous injection neoplastic cell overexpression particle protein structure public health relevance tool tumor vector

项目摘要

DESCRIPTION (provided by applicant): Intravenous delivery of recombinant adenovirus (Ad) vectors for gene therapy is hampered by safety and efficacy problems. We have recently discovered a new pathway that is involved in unspecific sequestration and clearance of commonly used Ad5 and Ad B-group virus Ad11-derived vectors in mice. Rapidly after intravenous administration, Ad5 and Ad11 bind to circulating platelets in a fiber-independent manner. Virus binding results in activation/aggregation of platelets and trapping in micro-blood vessels of the liver, where the virus-platelet aggregates are taken up by Kupffer cells. Ad sequestration in liver can be reduced by platelet depletion prior to vector injection. Platelet depletion increases transduction of liver metastases after intravenous Ad injection, which provides a rationale for studying the mechanism of Ad-platelet interaction with the final goal of constructing oncolytic Ad vectors that are ablated for platelet binding. The goals of this proposal are to identify the structural component/s within the virus capsid that are involved in Ad binding to platelets, and to produce vectors that are ablated for platelet binding. The central hypothesis is that these modified vectors are more efficient in transduction of metastatic tumors after intravenous injection. Although platelet-mediated degradation occurs for both Ad5 and Ad11 vectors, in this proposal, we will focus on modifying Ad11 because of its stronger binding to platelets which might facilitate studying Ad-platelet interactions. Moreover, Ad11-based vector are promising tools for gene therapy. Ad11 infects cells predominantly through CD46, and efficiently transduces important gene therapy targets that are refractory to infection with Ad5 vectors, such as tumor, dendritic, and tissue stem cells. Other advantages of Ad11 over Ad5 vectors include the lower serum prevalence of neutralizing anti-Ad11 antibodies and absence of liver transduction after intravenous vector application. Studies in this proposal will be done in mice that express CD46 in a human like pattern and in mice that contain human platelets. Public Health Relevance: The final aim of this proposal is to produce Ad11 vectors (Ad11?) that are ablated for binding to platelets. The outcome of this study will be relevant for Ad11 mediated tumor gene therapy and vaccination and potentially for the modification of Ad vectors based on other serotypes.

描述（由申请人提供）：用于基因治疗的重组腺病毒（Ad）载体的静脉内递送因安全性和有效性问题而受到阻碍。我们最近发现了一条新途径，该途径参与小鼠体内常用的 Ad5 和 Ad B 组病毒 Ad11 衍生载体的非特异性隔离和清除。静脉注射后，Ad5 和 Ad11 会以不依赖纤维的方式迅速与循环血小板结合。病毒结合导致血小板活化/聚集并捕获在肝脏的微血管中，其中病毒-血小板聚集体被库普弗细胞吸收。在注射载体之前去除血小板可以减少肝脏中的广告隔离。静脉注射Ad后，血小板耗竭增加了肝转移的转导，这为研究Ad-血小板相互作用的机制提供了理论依据，最终目标是构建可消除血小板结合的溶瘤Ad载体。该提案的目标是鉴定病毒衣壳内参与 Ad 与血小板结合的结构成分，并产生用于血小板结合的载体。中心假设是这些修饰的载体在静脉注射后更有效地转导转移性肿瘤。尽管 Ad5 和 Ad11 载体都会发生血小板介导的降解，但在本提案中，我们将重点关注 Ad11 的修饰，因为它与血小板的结合更强，这可能有助于研究 Ad-血小板相互作用。此外，基于 Ad11 的载体是有前途的基因治疗工具。 Ad11 主要通过 CD46 感染细胞，并有效转导对 Ad5 载体感染无效的重要基因治疗靶点，例如肿瘤、树突状细胞和组织干细胞。 Ad11 相对于 Ad5 载体的其他优点包括中和抗 Ad11 抗体的血清流行率较低以及静脉注射载体应用后不存在肝转导。该提案中的研究将在以类似人类模式表达 CD46 的小鼠和含有人类血小板的小鼠中进行。公共健康相关性：该提案的最终目标是生产经过消融后与血小板结合的 Ad11 载体（Ad11？）。这项研究的结果将与 Ad11 介导的肿瘤基因治疗和疫苗接种相关，并可能与基于其他血清型的 Ad 载体的修饰相关。