Recombinant, conditionally replication-defective adenovirus vectors have been employed to introduce a wide variety of recombinant genes both in vitro and in vivo. Recombinant adenovirus is a particularly attractive vector for direct somatic cell gene transfer in vivo by virtue of i) very high efficiency, and ii) independence of the growth state of the targeted cell population. However, adenovirus promiscuously infects a wide variety of cell and tissue types. While this has facilitated the development of adenovirus as a gene transfer vector, it is also an important limitation of these vectors for therapeutic gene transfer. An ideal gene transfer strategy, by contrast, would provide a mechanism to target delivery and expression of the foreign gene to particular tissues or organs in vivo and in situ. The primary objective of our research studies is to develop a strategy to target adenoviral-mediated gene transfer to specific tissues and/or cell types by modifying the interaction of the virus with the cell. Specifically, the aim is to utilize the information gained from molecular and structural studies to produce a ?smart virus?, a targeted adenovirus in which the knob domain of the fiber capsid protein is genetically modified by substitution with a polypeptide ligand with affinity for a particular cellular receptor expressed only by a specific cell type, thereby generating a tissue-specific gene transfer vector. Alternatively, we are using bispecific antibodies to retarget the virus to particular receptors. The strategy to be employed uses bispecific antibodies constructed using standard methods. The bispecific antibodies we currently are focused on are comprised of a neutralizing anti-fiber knob mAb paired with a mAb specific for vascular endothelium or tumor cells in an attempt to retarget the virus to tumors in vitro and in vivo. We anticipate that these targeting strategies will ultimately be useful for both tumor imaging and therapy.
RESEARCH INTERESTS
Vector Targeting
Adenovirus Vectors
Tumor Metastasis
Tumor Imaging
RECENT PUBLICATIONS
Varenne O, P Sinnaeve, H Gillijns, B Iung, V Laurysens, K Meurrens, B Bout, D Valerio, D Collen, SP Janssens and RD Gerard, "Percutaneous gene therapy using recombinant adenovirus vectors encoding human herpes simplex virus thymidine kinase, human PAI-1 and human NOS3 in balloon-injured porcine coronary arteries" Human Gene Therapy, 11:1329-1339, June 2000
Praus M, D Collen, RD Gerard, "Both u-PA inhibitory and vitronectin binding by plasminogen activator inhibitor 1 regulate tumor cell metastasis in vivo" International Journal of Cancer, 102:584-591, December 2002
Graf GA, W-P Li, RD Gerard, I Gelissen, A White, JC Cohen and HH Hobbs, "Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface" Journal of Clinical Investigation, 110:659-669, October 2002
Israel B, R Pickles, D Segal, RD Gerard, S Sweeney, "Enhancement of adenoviral vector entry into CD70-positive B cell lines using bispecific CD70/adenovirus fiber antibody" Journal of Virology, 75:5215-5221, August 2001
Xia, D, L Henry, RD Gerard and J Deisenhofer, "Structure of the adenovirus 5 fiber knob domain at 1.7E resolution" Structure, 2:1259-1270, June 1994
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