Her2-targeted vectors for gene therapy of cancer

用于癌症基因治疗的 Her2 靶向载体

基本信息

批准号：
7227154
负责人：
VICTOR KRASNYKH
金额：
$ 30.06万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2005-07-18 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227154
关键词：
Adenovirus Vector Adenoviruses Affinity Americas Animals Binding Binding Proteins Biodistribution Biological Biological Markers Breast Cancer Model Cancer Etiology Cancer Intervention Cancer Patient Capsid Characteristics Class Clinical Colon Developed Countries Development Directed Molecular Evolution Disease Disease regression Engineered Gene Engineering Fiber Future Gene Delivery Gene Transduction Agent Gene Transfer Genes Genetic Genus Cola Goals Health Human Image Imaging technology Immune response In Vitro Intervention Ligands Living Wills Localized Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Methodology Modification Molecular Monitor Multimodal Imaging Mus Nature Normal Cell Normal tissue morphology Patients Principal Investigator Process Prostate Protein Engineering Proteins Rate Research Research Personnel Safety Specificity Surface Therapeutic Time Toxic effect Transgenes Translations Treatment-Related Cancer Tropism Tumor Markers Viral Viral Vector Virion Virus Work base cancer therapy design expectation expression vector gene therapy improved malignant breast neoplasm molecular imaging mortality neoplastic cell new technology particle pre-clinical programs prototype receptor binding success therapeutic gene transgene expression tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): The research proposed here will solve two major problems that currently limit the development of effective gene therapy for cancer: a lack of tumor-selective gene delivery by the gene vectors and inadequate means to monitor this process and its consequences. The first problem will be overcome through the development of a new class of tumor-specific adenovirus vectors whose natural tropism will be modified to target these agents to Her2, a recognized tumor marker. The work will have three major components, each drawing on the specific expertise of the Principal Investigator and Co-Investigators. First, a novel technology for designing proteins will be used to develop highly specific ligands that will bind to Her2 with high affinity. Importantly, this will be the first time these new molecules have been used in gene therapy in general and in vector design in particular. Next, two alternative targeting strategies will be used to genetically incorporate these ligands into the capsid of the adenovirus. After these vectors have been extensively characterized in vitro, they will be employed in tumor treatment studies in animals. This final aspect of the research proposed here will involve the extensive use of modern molecular imaging technology to monitor viral spread, as well as the efficacy and specificity of gene delivery. This work will result in the design of adenovirus vectors suitable for gene therapy that are truly targeted to a variety of Her2-expressing human tumors. The tumor selectivity, efficacy of gene delivery, and safety of these vectors will be greatly improved as a result. This developmental work will make future gene therapy interventions for cancer more efficient and safe, and elucidate their mechanisms of action and their consequences. The development of targeted Ad vectors proposed herein will thus be a major advance in cancer treatment. Moreover, such vectors would be of great utility in the wider field of gene therapy by serving as a prototype in the development of gene therapy for other diseases.

描述（由申请人提供）：此处提出的研究将解决两个主要问题，目前限制了有效的癌症基因治疗的发展：基因载体缺乏肿瘤选择性基因递送，而不足的方法是监测此过程及其后果。第一个问题将通过开发新的肿瘤特异性腺病毒载体来克服，这些肿瘤特异性腺病毒载体将被修改为将这些药物靶向HER2，这是公认的肿瘤标记。这项工作将有三个主要组成部分，每个组成部分都借鉴了主要研究员和共同研究人员的具体专业知识。首先，设计蛋白质的新技术将用于开发具有高亲和力与HER2结合的高度特异性配体。重要的是，这将是这些新分子首次在基因治疗中，尤其是在媒介设计中。接下来，将使用两种替代靶向策略将这些配体纳入腺病毒的衣壳中。在这些载体在体外进行广泛表征之后，它们将用于动物的肿瘤治疗研究。此处提出的研究的最后一个方面将涉及现代分子成像技术的广泛使用来监测病毒传播，以及基因递送的功效和特异性。这项工作将导致设计适合基因疗法的腺病毒载体，这些腺病毒载体真正针对各种表达HER2的人类肿瘤。结果将大大提高肿瘤的选择性，基因递送的功效和这些载体的安全性。这项发展工作将使对癌症的未来基因治疗干预措施更加有效，安全，并阐明其作用机理及其后果。因此，本文提出的有针对性的AD向量的发展将是癌症治疗的重大进步。此外，通过作为开发其他疾病基因疗法的原型，这种载体在更广泛的基因治疗领域将具有很大的实用性。