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: 8193069
• 负责人: VICTOR KRASNYKH
• 金额: $ 31万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193069
• 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癌症基因疗法的最重要障碍。迫切需要开发能够选择性、高效和安全地将基因递送至肿瘤的载体。在满足这一需求之前，基因疗法所代表的癌症治疗范式转变将仍未实现。因此，该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载体的开发来提高癌症治疗的功效。为此，本提案的目标是开发一种基因传递策略，选择性地靶向肿瘤细胞，同时克服宿主的抗载体免疫性并降低正常组织的不良转导水平。要测试的中心假设是，这一目标可以通过使用多种向性修饰策略连续使用免疫学上不同的腺病毒（Ad）载体靶向肿瘤来实现。这项研究的基本原理是，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一个重要的垂直步骤。将测试中心假设，从而通过实现两个具体目标来实现该项目的目标： 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.测试设计的载体在抗Ad免疫存在下重复靶向肿瘤的能力。在这个项目中，代表这些分子天然多样性的一组不同的受体结合Ad纤维蛋白将被基因改造以靶向人类肿瘤上的主要分子标记，即Her2受体。这些蛋白质将通过使用新颖的、合理设计的蛋白质配体、亲和体而成为Her2特异性的，其大小、生物合成、稳定性和高亲和力使它们特别适合Ad载体靶向。为了制造这些纤维-亲和体嵌合体，我们将使用一种基于 Ad 纤维结构进化保守性的新型靶向策略，从而适用于各种 Ad 血清型。将测试所设计纤维的关键结构和功能特征，以确认其是否适合广告定位。接下来，将生成一组包含这些设计的蛋白质的 Her2 靶向 Ad 载体，并使用表达 Her2 的肿瘤细胞进行体外测试。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，但将基因重复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关键可行性将具有重大意义，因为它将为开发人类有效的基因干预措施打开大门，从而促进该技术转化为临床应用。我们的初步研究结果、研究团队的集体专业知识以及德克萨斯大学 M.D. 安德森癌症中心卓越的研究环境支持了拟议工作的成功。 公共健康相关性：拟议的研究与公共健康直接相关，因为它寻求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有可能重复、有效地将基因治疗和诊断试剂递送到癌症患者的靶肿瘤上，由于缺乏合适的基因递送载体，大多数患者目前无法从基因干预中受益。