875. Adenoviral Vector Targeting – New Targets for Old Capsids

Abstract

Top of pageAbstract The goal of our adenoviral vector-targeting program is to identify strategies that enhance delivery of therapeutic proteins to the site of disease as well as reduce the impact of the therapy on nontarget cells and tissue. Therapeutic areas under consideration are cancer, ocular disease, vaccine, hearing loss and balance disorders. To accomplish this we have created vectors that are ablated for binding to native CAR and integrin receptors, have introduced specific binding ligands for selective entry into the cells of choice, and have evaluated vector performance in these target therapeutic areas. We have evaluated the pharmacokinetics and biodistribution of tropism-modified vectors in regional (intra-peritoneal) and disseminated cancer disease models and have shown the importance of selective delivery to tumors after regional and systemic administration. Delivery to the eye and ear of tropism-modified vectors results in transduction of new target cells and the modifications may also impact the kinetics of transgene expression. We have demonstrated low-level expression of the normal entry receptors for adenovirus in the inner ear of mice, which is inconsistent with the amount of gene delivery observed by native tropism vectors. Adenovirus capsids ablated of normal receptor interactions (CAR and integrin) are still capable of gene delivery, suggesting that vector entry may occur through alternative pathways. The efficiency of gene delivery in the inner ear by capsid-modified vectors is dependent on target volume and local vector concentration. While efficient delivery within the inner ear is retained by the ablated vector, it has a restricted tropism for gene delivery to tissue outside of the inner ear. These results collectively lend support to the design of targeted adenovirus vectors that could enhance the delivery of the therapeutic protein and thereby be used for multiple clinical applications.