The liver is a key organ in numerous metabolic pathways, in cholesterol metabolism, and in production of coagulation factors. Therefore, gene transfer to hepatocytes has been extensively pursued. There are numerous biological parameters that may affect the outcome of hepatocyte-directed gene transfer. Species or strain variation of any of these multiple determinants hinders the process of clinical translation. This review specifically focuses on functional aspects of liver histology that are pertinent for gene transfer to parenchymal liver cells. We discuss the reticulo-endothelial cells of the liver and the spleen, and their impact on innate immune responses after adenoviral transfer and on vector clearance. Liver sinusoidal endothelial cells contain pores, called fenestrae, and have no basal lamina. Fenestrae are clustered in sieve plates and may provide direct access for circulating gene transfer vectors to the space of Disse, in which microvilli of parenchymal liver cells protrude. We present multiple lines of evidence that the species differences in the diameter of sinusoidal fenestrae are a critical determinant of transgene expression after adenoviral transfer. The small diameter of fenestrae in humans should be considered in any rational design of gene transfer technologies for hepatocyte-directed transfer. Hydrodynamic gene transfer is highly successful in rodents. The significantly lower efficacy in higher species may also partially be due to species differences in liver architecture. Finally, we discuss species differences in adaptive immune responses against the transgene product that may constitute one of the most significant hurdles for clinical translation.
Keywords: Gene transfer, liver, fenestrae, species, adenoviral vector, hepatocyte, reticulo-endothelial system, sinusoid
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