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.
