1. ¹Division of Human Gene Therapy, Departments of Medicine, Obstetric and Gynecology, Pathology and Surgery, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA
2. ²Department of Pathology, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Dr DT Curiel, Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. E-mail: david.curiel@ccc.uab.edu

Received 14 August 2006; Revised 25 October 2006; Accepted 26 November 2006; Published online 25 January 2007.

Abstract

Adenovirus (Ad)-based vectors are useful gene delivery vehicles for a variety of applications. Despite their attractive properties, many in vivo applications require modulation of the viral tropism. Targeting approaches applied to adenoviral vectors included genetic modification of the viral capsid, controlled expression of the transgene and combinatorial approaches that combine two or more targeting elements in single vectors. Most of these studies confirmed successful retargeting in cell cultures, however, in vivo gains of targeted adenoviral vectors have not been widely demonstrated. We have developed a combinatorial retargeting approach utilizing metabolically biotinylated Ad, where the biotin acceptor peptide was incorporated in one of the fibers in a dual fiber viral particle resulting in metabolically biotinylated fiber-mosaic Ad (mBfMAd). We have utilized this vector in complex with epidermal growth factor (EGF)-Streptavidin to retarget fiber-mosaic virus to EGF receptor (EGFR) expressing cells in vitro and confirmed an increased infectivity of the retargeting complex. Most importantly, the utility of this strategy was demonstrated in vivo in two distinct animal models. In both models tested, retargeted mBfMAd demonstrated an increased ratio of gene expression in target tissues compared to the liver expression profile. Thus, metabolically biotinylated fiber-mosaic virus in combination with appropriate adapters can be successfully exploited for adenoviral retargeting strategies.