Biodistribution of adenoviral vector to nontarget tissues after local in vivo gene transfer to arterial wall using intravascular and periadventitial gene delivery methods

Expression of transgene other than in the target tissue may cause side effe cts and safety problems in gene therapy. We analyzed biodistribution of tra nsgene expression after intravascular and periadventitial gene delivery met hods using the first generation nuclear-targeted lacZ adenovirus. RT-PCR an d X-Gal stainings were used to study transgene expression 14 days after the gene transfer. After intravascular catheter-mediated gene transfer to rabb it aorta mimicking angioplasty procedure, the target vessel showed 1.1% +/- 0.5 gene transfer efficiency. Other tissues showed varying lacZ gene expre ssion indicating a systemic leakage of the vector with the highest transfec tion efficiency in hepatocytes (0.7% +/- 0.5). X-Gal staining of blood cell s 24 h after the intravascular gene transfer indicated that a significant p ortion (1.8% +/- 0.8) of circulating monocytes was transfected. X-Gal-posit ive cells were also found in testis. After periadventitial gene transfer us ing a closed silicon capsule placed around the artery, 0.1% +/- 0.1 lacZ-po sitive cells were detected in the artery wall. Positive cells were also fou nd in the liver and testis (<0.01%), indicating that the virus escapes even from the periadventitial space, although less extensively than during the intravascular application. We conclude that catheter-mediated intravascular and, to a lesser extent, periadventitial gene transfer lead to leakage of adenovirus to systemic circulation, followed by expression of the transgene in several tissues. Possible consequences of the ectopic expression of the transgene should be evaluated in gene therapy trials even if local gene de livery methods are used.