The objective of the proposed research is to test the concept of engineering the fiber protein of adenovirus to target adenovirus gene delivery vectors via cell type specific receptors. Our approach is to modify the adenovirus fiber protein by replacing the fiber head domain with ligands which bind to known cellular receptors which may be expressed in a cell specific manner. Modified fiber proteins will initially be expressed in vitro and in insect cells. The structure and receptor binding properties of chimeric fiber proteins will be assessed to determine whether the desired specificity has been achieved. Modified fibers will subsequently be introduced into the adenovirus genome using an adenovirus YAC and the viability and cellular specificity of mutant adenoviruses will be assessed. The use of this approach to target adenovirus vectors carrying therapeutic genes such as the HSV-tk gene to tumor cells will be evaluated.
Adenoviruses show considerable promise as gene therapy vectors for treatment of a variety of inherited and acquired diseases. This research proposal is aimed towards improvements in gene delivery technology using adenovirus based vectors. A new generation of adenovirus vectors engineered to deliver their genetic content to specific cell types via selective receptor binding is envisaged. This could lead to commercial opportunities through improvements in the efficacy and safety of adenovirus vectors for gene therapy of a variety of disease.
