Multi-serotype adenovirus vector system for targeted gene delivery to tumors

用于肿瘤靶向基因递送的多血清型腺病毒载体系统

• 批准号: 7894906
• 负责人: VICTOR KRASNYKH
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2011-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894906
• 关键词: Adenovirus Vector; Adenovirus hexon capsid protein; Adenoviruses; Affinity; Anabolism; Animal Model; Bypass; Cancer Patient; Cessation of life; Chimera organism; Clinical; Communities; Data; Development; Diagnostic; Disease; Environment; Fiber; Gene Delivery; Gene Transfer; Generations; Genes; Genetic; Goals; Health; Human; Human Adenoviruses; Image; Immune response; Immunity; Immunologics; Incidence; Intervention; Life; Ligands; Malignant Neoplasms; Modification; Molecular; Normal tissue morphology; Oncogenes; Outcome; Plague; Preparation; Proteins; Public Health; Reagent; Regimen; Research; Resources; Serotyping; Specificity; Structure; Study Section; System; Technology; Testing; Time; Tissues; Transgenic Animals; Translations; Tropism; United States; United States National Institutes of Health; University of Texas M D Anderson Cancer Center; Virion; Work; base; cancer diagnosis; cancer therapy; cancer type; design; fighting; gene delivery system; gene therapy; immunogenicity; improved; in vitro testing; innovation; malignant breast neoplasm; meetings; molecular marker; mortality; neoplastic cell; new technology; novel; programs; public health relevance; receptor; receptor binding; success; therapeutic gene; tumor; vector

DESCRIPTION (provided by applicant): The lack of efficient gene delivery systems is the most important barrier to the use of gene therapy for cancer. There is an urgent need to develop vectors that are capable of selective, efficient, and safe delivery of genes to tumors. Until this need is met, the paradigm shift in cancer treatment that gene therapy represents will remain unrealized. It is thus the long-term goal of this research program to improve the efficacy of cancer treatment by facilitating the development of a new generation of improved vectors for cancer gene therapy. Toward this end, the objective of this proposal is to develop a gene-delivery strategy that will selectively target tumor cells while concomitantly overcoming the anti-vector immunity of the host and reducing the level of undesired transduction of normal tissues. The central hypothesis to be tested is that this objective can be accomplished through sequential use of immunologically distinct adenovirus (Ad) vectors targeted to tumors using a versatile strategy of tropism modification. The rationale for this study is that overcoming the vector immunogenicity and specificity problems will be a major vertical step toward making cancer gene therapy a clinical reality. The central hypothesis will be tested and thereby the objective of this project will be achieved by realizing two specific aims: Specific Aim 1. Develop a panel of antigenically distinct tumor-targeted Ad vectors. Specific Aim 2. Test the ability of the designed vectors to repeatedly target tumors in the presence of anti-Ad immunity. In this project, a diverse panel of receptor- binding Ad fiber proteins that represent the natural diversity of these molecules will be genetically modified to target a major molecular marker on human tumors, the Her2 receptor. These proteins will be made Her2- specific through the use of novel, rationally designed protein ligands, affibodies, whose size, biosynthesis, stability, and high affinity make them uniquely suited for Ad vector targeting. To make these fiber-affibody chimeras, we will use a novel targeting strategy based on the evolutionary conservation of the Ad fiber structure and thus applicable to a variety of Ad serotypes. The key structural and functional features of the designed fibers will be tested to confirm their suitability for Ad targeting. Next, a panel of Her2-targeted Ad vectors containing these designed proteins will be generated and tested in vitro using Her2-expressing tumor cells. Last, through the use of these new vectors in a transgenic animal model of breast cancer, we will demonstrate the feasibility of repeated gene delivery to target tumors despite preexisting anti-Ad immunity. This first demonstration of this key feasibility of gene therapy paradigm in our study will be of major significance because it will open the door to the development of efficacious gene interventions in humans, thereby facilitating the translation of this technology into clinical use. The success of the proposed work is supported by our preliminary findings, the collective expertise of our research team, and the exceptional research environment at The University of Texas M. D. Anderson Cancer Center. PUBLIC HEALTH RELEVANCE: The proposed research is directly relevant to public health because it seeks to develop a new genetic strategy of treating and imaging human tumors. Accomplishing this goal will make it possible for the first time to repeatedly and efficiently deliver gene therapeutic and diagnostic agents to target tumors in cancer patients, most of who cannot benefit from genetic interventions at present because of the lack of appropriate gene delivery vehicles.

描述（由申请人提供）：缺乏有效的基因递送系统是使用基因治疗癌症的最重要障碍。迫切需要开发能够选择性、有效和安全地将基因递送至肿瘤的载体。在这一需求得到满足之前，基因治疗所代表的癌症治疗模式的转变将仍然无法实现。因此，本研究计划的长期目标是通过促进新一代癌症基因治疗载体的开发来提高癌症治疗的疗效。为此，本提案的目的是开发一种基因递送策略，该策略将选择性地靶向肿瘤细胞，同时克服宿主的抗载体免疫并降低正常组织的不期望的转导水平。要测试的中心假设是，这一目标可以通过连续使用免疫学上不同的腺病毒（Ad）载体靶向肿瘤使用一个通用的嗜性修饰策略来实现。这项研究的基本原理是，克服载体的免疫原性和特异性问题将是一个主要的垂直步骤，使癌症基因治疗的临床现实。将对中心假设进行检验，从而通过实现两个具体目标来实现本项目的目标：具体目标1。开发一组抗原性不同的肿瘤靶向Ad载体。具体目标2。测试所设计的载体在抗Ad免疫存在下重复靶向肿瘤的能力。在该项目中，代表这些分子的天然多样性的受体结合Ad纤维蛋白的多样性小组将被遗传修饰以靶向人类肿瘤上的主要分子标记物Her 2受体。这些蛋白质将通过使用新的、合理设计的蛋白质配体（其大小、生物合成、稳定性和高亲和力使其独特地适合于Ad载体靶向）而成为Her 2特异性的。为了制造这些纤维-杆状体嵌合体，我们将使用基于Ad纤维结构的进化保守性的新型靶向策略，从而适用于各种Ad血清型。设计的纤维的关键结构和功能特征将被测试，以确认它们对Ad靶向的适用性。接下来，将使用表达Her 2的肿瘤细胞产生并在体外测试一组含有这些设计的蛋白质的Her 2靶向Ad载体。最后，通过在乳腺癌转基因动物模型中使用这些新载体，我们将证明尽管预先存在抗Ad免疫，重复基因递送至靶肿瘤的可行性。在我们的研究中首次证明基因治疗范式的这种关键可行性将具有重大意义，因为它将为人类有效基因干预的发展打开大门，从而促进这项技术转化为临床应用。拟议工作的成功得到了我们的初步发现，我们研究团队的集体专业知识以及德克萨斯大学M。D.安德森癌症中心。 公共卫生关系：这项研究与公共卫生直接相关，因为它旨在开发一种治疗和成像人类肿瘤的新遗传策略。实现这一目标将首次使重复和有效地将基因治疗和诊断剂递送到癌症患者的靶向肿瘤成为可能，由于缺乏适当的基因递送载体，目前大多数癌症患者无法从基因干预中获益。