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）：缺乏有效的基因输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，高效且安全地传递基因向肿瘤的媒介。在满足这种需求之前，基因治疗所代表的癌症治疗的范式转移将保持未实现。因此，这项研究计划的长期目标是通过促进新一代改进的癌症基因治疗媒介来提高癌症治疗的功效。为此，该提案的目的是制定一种基因分娩策略，该策略将有选择地靶向肿瘤细胞，同时同时克服宿主的抗载体免疫，并降低正常组织的不需要的转导水平。要测试的中心假设是，可以通过使用多功能性的对肿瘤的多功能策略修改靶向肿瘤的免疫学上不同的腺病毒（AD）向量来实现该目标。这项研究的理由是克服载体免疫原性和特异性问题将是使癌症基因治疗成为临床现实的主要垂直步骤。将测试中心假设，从而通过实现两个特定目的来实现该项目的目标：特定目标1。开发一组抗原截然不同的肿瘤靶向AD载体。具体目标2。在存在抗AD免疫力的情况下，测试设计载体反复靶向肿瘤的能力。在这个项目中，代表这些分子的自然多样性的多种受体结合AD纤维蛋白将经过遗传修饰，以靶向人类肿瘤HER2受体的主要分子标记。这些蛋白质将通过使用新颖的，理性设计的蛋白质配体，附属蛋白（其大小，生物合成，稳定性和高亲和力）使其具有特定于HER2的特异性。为了制造这些纤维受伤的嵌合体，我们将基于对AD纤维结构的进化保护使用新颖的靶向策略，因此适用于各种AD血清型。将测试设计纤维的关键结构和功能功能，以确认其适合广告靶向的性能。接下来，将使用表达HER2的肿瘤细胞在体外生成和测试一群包含这些设计蛋白的HER2靶向AD载体。最后，通过在乳腺癌的转基因动物模型中使用这些新载体，我们将证明，尽管已经存在抗AD免疫，但反复基因递送至靶向肿瘤的可行性。在我们的研究中，首次展示了基因治疗范式的这种关键可行性，这将具有重要意义，因为它将为人类有效基因干预的发展打开大门，从而促进该技术转化为临床使用。我们的初步发现，研究团队的集体专业知识以及德克萨斯大学M. D. Anderson Cancer Center的杰出研究环境为拟议工作的成功提供了支持。 公共卫生相关性：拟议的研究与公共卫生直接相关，因为它试图制定一种治疗和成像人类肿瘤的新遗传策略。实现这一目标将使首次有可能反复有效地提供基因治疗和诊断剂来靶向癌症患者的肿瘤，因为缺乏适当的基因递送车，目前大多数人目前无法从遗传干预中受益。