Evaluation of Vectors based on group B adenoviruses

基于B组腺病毒的载体评价

基本信息

批准号：
7784902
负责人：
ANDRE Michael LIEBER
金额：
$ 32.37万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7784902
关键词：
Adenoviruses Adherence Adherens Junction Affect Affinity Antibodies Binding Biodistribution C-terminal CAR receptor CD46 Antigen Cell Culture Techniques Cell Membrane Proteins Cell membrane Cells Chelating Agents Chemicals Complex Data Detergents Disease Outbreaks Dominant-Negative Mutation Drug Delivery Systems Drug Transport Ectopic Expression Electron Microscopy Engineering Epithelial Epithelial Cells Epithelial ovarian cancer Evaluation Extracellular Space Fiber Gene Transduction Agent Gene Transfer Genes Glycoproteins Glycosaminoglycans Goals Gold Heparan Sulfate Proteoglycan Heparitin Sulfate Human Immune Immunofluorescence Microscopy Infection Insecta Knowledge Lateral Libraries Link Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Measurement Mediating Messenger RNA Modality Modeling Molecular Conformation Mouse Strains Mus Mutagenesis Mutation Oncogenes Oncolytic Patients Peptides Perfusion Pharmaceutical Preparations Phenotype Phospholipids Production Protein Engineering Proteins Recombinants Research Resistance Role Scaffolding Protein Screening procedure Series Serotyping Signal Pathway Signal Transduction Small Interfering RNA Solid Staining method Stains Techniques Tertiary Protein Structure Therapeutic Tight Junctions Tissues Toxic effect Toxin Transgenic Organisms Variant Virion Virus X-Ray Crystallography adenovirus penton protein antitumor agent base cancer cell chemotherapy design directed evolution gain of function gene therapy glycosaminoglycan receptor immunogenicity in vivo inhibitor/antagonist killings loss of function member migration mouse model mutant neoplastic cell oncolytic vector pathogen penton base polysulfated glycosaminoglycan prevent public health relevance receptor scaffold seal surfactant tool tumor uptake vector virology

项目摘要

DESCRIPTION (provided by applicant): The majority of solid cancers are of epithelial origin. A hallmark of epithelial cells are tight and adherens junctions. Tight and adherens junctions seal intercellular spaces and significantly limit the perfusion of anti- tumor agents such as drugs, antibodies, and immune cells within the tumor, thus severely diminishing the efficacy of such therapeutic modalities. The epithelial phenotype of cancer cells also represents a barrier to infection with commonly used adenoviruses (Ads) that target CD46 or the coxsackie-adenovirus receptor (CAR), due to trapping of these receptors in tight and adherens junctions which explains, in part, why these serotypes are inefficient in cancer gene therapy. We found however, that specific human species B adenoviruses, namely Ad3, Ad7, Ad11, and Ad14 (AdB-group 2) that use a yet unknown receptor (receptor X), which is different from CAR and CD46, efficiently infect epithelial cancer cells. This makes these serotypes potential tools for virotherapy of cancer as well as for gene transfer into normal epithelial tissue. In addition, these serotypes are important pathogens, exemplified by recent outbreaks of a highly pathogenic new Ad14 stain (Ad14a) that also uses receptor X. Furthermore, we have shown that recombinant Ad3 dodecahedra (PtDd) formed through interaction of 12 penton bases with protruding fibers can enter epithelial cancer cells and faciliate uptake of Ads (and potentially other tumor agents) for which tight and adherens junctions represent a barrier. Based on the importance of Ad3, 7, 11, and 14 as pathogens and potential vectors for gene therapy, the central goals of this proposal are to identify receptor X, to delineate the mechanism of AdB- group 2 and PtDd uptake in normal and malignant epithelial cells, and to develop AdB-group 2 vectors and PtDd-derivatives as vehicles for gene or drug delivery into epithelial cancers. PUBLIC HEALTH RELEVANCE: In cancers of epithelial origin, tight and adherens junctions seal intercellular spaces and severely diminish the efficacy of anti-tumor agents. The central goals of this proposal are to understand how adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 infect normal and malignant epithelial cells and to develop derivatives of these adenoviruses as vehicles for gene or drug delivery into epithelial cancers.

描述（由申请人提供）：大多数实体癌是上皮来源的。上皮细胞的一个标志是紧密且粘附的连接。紧密且粘附的连接密封了细胞间隙并显着限制了抗肿瘤剂（例如药物、抗体和免疫细胞）在肿瘤内的灌注，从而严重削弱了此类治疗方式的功效。癌细胞的上皮表型也代表了针对 CD46 或柯萨奇腺病毒受体 (CAR) 的常用腺病毒 (Ad) 感染的屏障，因为这些受体被捕获在紧密和粘附的连接中，这在一定程度上解释了为什么这些血清型在癌症基因治疗中效率低下。然而，我们发现，特定的人类 B 类腺病毒，即 Ad3、Ad7、Ad11 和 Ad14（AdB 组 2）使用与 CAR 和 CD46 不同的未知受体（受体 X），可有效感染上皮癌细胞。这使得这些血清型成为癌症病毒疗法以及将基因转移到正常上皮组织的潜在工具。此外，这些血清型是重要的病原体，例如最近爆发的高致病性新Ad14染色剂（Ad14a）也使用受体X。此外，我们还发现重组Ad3十二面体（PtDd）是通过12个五邻体碱基与突出的相互作用形成的纤维可以进入上皮癌细胞并促进广告（以及潜在的其他肿瘤药物）的吸收，而紧密和粘附的连接是其屏障。基于 Ad3、7、11 和 14 作为病原体和基因治疗潜在载体的重要性，该提案的中心目标是鉴定受体 X，以描述正常和恶性细胞中 AdB-2 组和 PtDd 摄取的机制。上皮细胞，并开发 AdB-group 2 载体和 PtDd-衍生物作为基因或药物递送至上皮癌的载体。公共健康相关性：在上皮来源的癌症中，紧密和粘附的连接会密封细胞间隙并严重降低抗肿瘤药物的功效。该提案的中心目标是了解腺病毒血清型 Ad3、Ad7、Ad11 和 Ad14 如何感染正常和恶性上皮细胞，并开发这些腺病毒的衍生物作为将基因或药物递送到上皮癌的载体。