Gene therapy using adenoviruses is limited by the inability to selectively deliver DNA to specific targets. Retargeting can be accomplished by introducing fibroblast growth factor (FGF) onto viral capsids through its conjugation to neutralizing anti-viral antibodies. As a result, vectors bind to cells not through their native receptors, but rather through FGF receptors overexpressed on tumors and proliferating endothelium. In addition, an increased transduction efficiency is accomplished, which we hypothesize results from the high affinity of FGF receptors (Kd= approximately 2 pM) and their ability to traffic to the nucleus. In this application we propose to examine the mechanisms of FGF retargeting in vitro.
Specific aim one will define the roles of FGF and adenoviral receptors in cell surface binding and transduction.
Specific aim two will confirm the intracellular pathways of virus internalization and gene delivery. Phase II studies would use this information to rationally develop in vivo models for examining the influence of FGF-retargeting on viral toxicity and immunogenicity, and for the development other ligand-viral conjugates. The data generated will validate the use of growth factor retargeting for gene therapy, and establish the groundwork required for its use in clinical trials.
The proposed studies are designed to develop therapeutic products for gene therapy. Initial drug candidates will target adenoviruses to growth factor receptors overexpressed on tumor cells and associated vasculature, while at the same time eliminating normal viral tropism for uninvolved organs. Targeted delivery will allow transduction of tumors with cytotoxic proteins and other anti-proliferative agents, and accomplish antitumor activity by destruction of tumor cells and/or proliferating endothelium. This approach will allow application of the growing number of adenoviral vectors to cancer gene therapy by eliminating their major limitation, namely non-targeted delivery to normal tissues.
| Hoganson, D K; Sosnowski, B A; Pierce, G F et al. (2001) Uptake of adenoviral vectors via fibroblast growth factor receptors involves intracellular pathways that differ from the targeting ligand. Mol Ther 3:105-12 |
| Doukas, J; Hoganson, D K; Ong, M et al. (1999) Retargeted delivery of adenoviral vectors through fibroblast growth factor receptors involves unique cellular pathways. FASEB J 13:1459-66 |
