Adenovirus interaction with platelets

腺病毒与血小板的相互作用

• 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
• 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

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）载体的静脉内递送受到安全性和有效性问题的阻碍。我们最近发现了一种新的途径，涉及非特异性隔离和清除常用的Ad 5和Ad B组病毒Ad 11衍生的载体在小鼠中。静脉给药后，Ad 5和Ad 11以非纤维依赖性方式与循环血小板结合。病毒结合导致血小板的活化/聚集并捕获在肝脏的微血管中，其中病毒-血小板聚集体被枯否细胞吸收。在载体注射之前通过血小板耗竭可以减少肝脏中的Ad隔离。静脉注射Ad后血小板耗竭增加肝转移的转导，这为研究Ad-血小板相互作用的机制提供了理论基础，最终目标是构建消融血小板结合的溶瘤Ad载体。该提议的目标是鉴定病毒衣壳内参与Ad与血小板结合的结构组分，并产生被消融以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内注射后在转移性肿瘤的转导中更有效。尽管Ad 5和Ad 11载体都发生血小板介导的降解，但在本提案中，我们将重点关注Ad 11的修饰，因为它与血小板的结合更强，这可能有助于研究Ad-platelet相互作用。此外，基于Ad 11的载体是有希望的基因治疗工具。Ad 11主要通过CD 46感染细胞，并有效地转导难以用Ad 5载体感染的重要基因治疗靶点，如肿瘤、树突状细胞和组织干细胞。与Ad 5载体相比，Ad 11的其他优势包括中和抗Ad 11抗体的血清流行率较低，以及静脉内载体应用后不存在肝脏转导。本提案中的研究将在以类似人类模式表达CD 46的小鼠和含有人类血小板的小鼠中进行。 公共卫生相关性：本提案的最终目的是生产Ad 11载体（Ad 11？）被切除后与血小板结合本研究的结果将与Ad 11介导的肿瘤基因治疗和疫苗接种相关，并可能用于基于其他血清型的Ad载体的修饰。