Her2-targeted vectors for gene therapy of cancer

描述（由申请人提供）：本文提出的研究将解决目前限制癌症有效基因治疗发展的两个主要问题：缺乏基因载体的肿瘤选择性基因递送和监测这一过程及其后果的手段不足。第一个问题将通过开发一类新的肿瘤特异性腺病毒载体来克服，该腺病毒载体的天然向性将被修改以将这些药剂靶向Her2（一种公认的肿瘤标志物）。这项工作将有三个主要部分，每个部分都利用主要研究者和共同研究者的具体专门知识。首先，设计蛋白质的新技术将用于开发高度特异性的配体，这些配体将以高亲和力与Her2结合。重要的是，这将是这些新分子首次用于基因治疗，特别是载体设计。接下来，将使用两种替代的靶向策略将这些配体遗传地并入腺病毒的衣壳中。在这些载体在体外进行了广泛的表征后，它们将用于动物肿瘤治疗研究。本文提出的研究的最后一个方面将涉及广泛使用现代分子成像技术来监测病毒传播，以及基因递送的有效性和特异性。这项工作将导致设计适合基因治疗的腺病毒载体，真正靶向各种表达Her2的人类肿瘤。因此，这些载体的肿瘤选择性、基因递送效率和安全性将大大提高。这一发展工作将使未来的癌症基因治疗干预更加有效和安全，并阐明其作用机制及其后果。因此，本文提出的靶向Ad载体的开发将是癌症治疗的主要进展。此外，这样的载体将在更广泛的基因治疗领域中具有很大的实用性，作为其他疾病的基因治疗开发的原型。

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.