Scientific Publications by FDA Staff

Gene Ther 2004 Mar;11(5):431-8

Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease.

Smith JS, Tian J, Muller J, Byrnes AP

Byrnes AP, FDA Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, HFM-725,8800 Rockville Pike,29B-2E20, Bethesda, MD 20892 USA FDA Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA

When adenovirus vectors are injected intravenously, most of the virions are quickly taken up by the reticuloendothelial system, primarily by the liver macrophages known as Kupffer cells. However, little is known about the behavior of adenovirus vectors when there is pre-existing liver disease. To study this, we examined the biodistribution of intravenously injected vector in a rat model of cirrhosis induced by bile duct ligation. Using quantitative PCR and fluorescently tagged adenovirus vectors, we observed a significant reduction in vector uptake by the cirrhotic liver and increased accumulation in the lungs. Immunocytochemistry and electron microscopy demonstrated that this was due to changes in the reticuloendothelial system, with the vector being taken up by large numbers of pulmonary intravascular macrophages in the lungs of cirrhotic rats. Interestingly, expression of vector-encoded luciferase was significantly reduced in the livers of cirrhotic rats, but was not increased in the lungs. These data demonstrate that the biodistribution of adenovirus vectors in rats is altered by cirrhosis, which suggests the possibility that these vectors might behave unexpectedly in patients with pre-existing liver conditions, particularly since pulmonary reticuloendothelial changes are known to occur in human disease.