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）：基因治疗的重组腺病毒（AD）向量的静脉输送受到安全性和功效问题的阻碍。我们最近发现了一种新的途径，该途径参与了小鼠中常用AD5和AD B组病毒AD11衍生的载体的非特异性隔离和清除率。静脉内给药后，AD5和AD11以纤维独立的方式与循环血小板结合。病毒结合会导致血小板激活/聚集肝脏的微血管中，其中库普弗细胞吸收了病毒 - 植物 - 斑点聚集体。在载体注射之前，可以通过血小板耗竭来减少肝脏中的AD隔离。血小板的耗竭增加了静脉注射后肝转移的转移，这为研究AD-PLATELET相互作用的机制提供了一种理论，其最终目标是构建用于血小板结合的溶瘤AD载体。该提案的目标是确定与血小板结合的病毒capsid中的结构成分，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移转移性肿瘤。尽管AD5和AD11载体都会发生血小板介导的降解，但在此提案中，我们将重点介绍AD11，因为它与血小板具有更强的结合，这可能有助于研究Ad-Platelet相互作用。此外，基于AD11的载体是基因治疗的有前途的工具。 AD11主要通过CD46感染细胞，并有效地转导重要的基因疗法靶标，这些靶标对于用AD5载体（例如肿瘤，树突状和组织干细胞）感染了感染。 AD11比AD5载体的其他优势包括中和抗AD11抗体的较低血清患病率以及静脉注射载体应用后缺乏肝脏转导的率。该提案中的研究将在像人类一样的人类和包含人血小板的小鼠中表达CD46的小鼠进行。公共卫生相关性：该提案的最终目的是生产aD11矢量（AD11？），该媒介被消融到与血小板结合的粘合剂。这项研究的结果将与AD11介导的肿瘤基因治疗和疫苗接种有关，并有可能根据其他血清型对AD矢量进行修饰。