It is the goal of this proposal to facilitate gene therapy for cardiovascular, pulmonary and hematological diseases by developing a systematically stable vector capable of efficient cell-specific gene delivery. It is our hypothesis that genetic modifications can be made to the adenoviral vector to alter native viral tropism in order to achieve selective transduction of target disease cells. The first specific aim is to prevent recognition of the fiber receptor by employing genetic methods to shorten the shaft of the fiber protein. The second specific aim is to identify the optimum site in the adenoviral hexon capsid protein for the incorporation of cell-specified targeting peptides. Having determined the feasibility of this strategy, in this phase I proposal, we will subsequently employ phage display libraries to identify peptides which exhibit specific binding to target cells affected by cardiovascular, pulmonary and hematological. These targeting peptides will be incorporated into the adenoviral vectors to accomplish cell-specific gene delivery. By addressing a key issue which limits the translation of present gene therapy strategies into clinical trials, the development of this targetable, injectable vector system would represent a major technical advance in gene therapy for cardiovascular, pulmonary and hematological diseases.
Adenoviral vectors are important gene transfer vehicles but their utility is limited by their inability to accomplish cell-specific gene delivery. This proposal will derive a """"""""targeted"""""""", cell-specific adenoviral vector. This modification of the adenovirus will greatly improve its utility and therefore its commercial potential.
