Molecular-genetic imaging and gene therapy that promise to revolutionize the management of human disease are currently inefficient because available gene vectors are suboptimal for clinical use. Therefore, the long-term objective of our research program is to facilitate the development of these modalities for disseminated cancers through the design of safe and efficient dual-function gene theranostics. As an important step toward this objective, the goal of this proposed research is to explore the possibility of substantial improvement of targeted intratumoral expression of therapeutic and imaging reporter genes by developing novel viral vectors that meet the requirements of tumor-specific transduction. We hypothesize that this goal can be accomplished through rational modification of the natural tropism of simian adenovirus (Ad) Pan7, whose unique biology makes it a preferred vector prototype for genetic interventions in humans. This hypothesis will be tested by accomplishing this Specific Aim: Explore the feasibility of efficient target-specific gene delivery to disseminated tumors through the use of hexon-modified Pan7 vectors. The experimental strategy to achieve this aim is to mimic the natural mechanism of the highly efficient transduction of liver tissue in vivo described for the human Ad type 5 (Ad5), which involves numerous receptor-binding ligands anchored to the viral hexon protein. To achieve highly efficient and target-specific delivery and expression of imaging and therapeutic genes, the main protein component of the Pan7 virion, the hexon, will be genetically modified to carry ligands specific for a molecular marker of human cancers. The specificity and efficacy of the proposed vectors will be tested and compared with those of the currently used vectors in an animal model of metastatic cancer using noninvasive optical imaging facilitated by the vector-encoded reporter gene expression. By yielding dual-function gene agents that will be able to locate and selectively transduce disseminated tumor metastases on vascular delivery, this project will improve diagnosis and treatment of disseminated malignant disease, which remains the major cause of cancer-related deaths. Furthermore, the proposed gene delivery strategy is expected to be suitable for molecular-genetic imaging and therapy of a broad range of diseases and will thus have a major impact on the management of human health. The success of this proposed work will be an important contribution to the developing field of gene medicine because it will provide the field with much-needed means of gene delivery, will establish a new strategy for designing such agents, and will thus facilitate and accelerate further development of these agents toward clinical applications.
The proposed study has direct relevance to public health because it will yield an efficient and safe vector platform for molecular-genetic imaging and the treatment of malignant disease. Successful completion of this research will enable efficient diagnosis and therapy of metastatic cancer, thus leading to saved and prolonged human life in the subpopulation of patients with highest risk.
|Belousova, Natalya; Mikheeva, Galina; Xiong, Chiyi et al. (2016) Native and engineered tropism of vectors derived from a rare species D adenovirus serotype 43. Oncotarget 7:53414-53429|
|Dreier, Birgit; Honegger, Annemarie; Hess, Christian et al. (2013) Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters. Proc Natl Acad Sci U S A 110:E869-77|