A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo

Adenoviral (Ad) vectors are promising gene therapy vehicles due to their in vivo stability and efficiency, but their potential utility is compromised by their restricted tropism. Targeting strategies have been devised to impr ove the efficacy of these agents, but specific targeting following in vivo systemic administration of vector has not previously been demonstrated. The distinct aim of the current study was to determine whether an Ad-targeting strategy could maintain fidelity upon systemic vascular administration. We used a bispecific antibody to target Ad infection specifically to angioten sin-converting enzyme (ACE), which is preferentially expressed on pulmonary capillary endothelium and which may thus enable gene therapy for pulmonary vascular disease. Cell-specific gene delivery to ACE-expressing cells was first confirmed in vitro. Administration of retargeted vector complex via t ail vein injection into rats resulted in at least a 20-fold increase in bot h Ad DNA localization and luciferase transgene expression in the lungs, com pared to the untargeted vector. Furthermore, targeting led to reduced trans gene expression in nontarget organs, especially the liver, where the reduct ion was over 80%. Immunohistochemical and immunoelectron microscopy analysi s confirmed that the pulmonary transgene expression was specifically locali zed to endothelial cells. Enhancement of transgene expression in the lungs as a result of the ACE-targeting strategy was also confirmed using a new no ninvasive imaging technique. This study shows that a retargeting approach c an indeed specifically modify the gene delivery properties of an Ad vector given systemically and thus has encouraging implications for the further de velopment of targetable, injectable Ad vectors.