Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae

The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

“…Visualization of fenestrae in transmission electron microscopy sections requires that endothelial cells and their sieve plates are cut tangentially so that fenestrae become visible as holes. Using this technology and standardized protocols, we have previously shown that the average diameter of fenestrae is significantly larger in Sprague Dawley rats (150 nm in the pericentral area and 175 nm in the periportal area) 44 and C57BL/6 mice (141 nm) 47 than in New Zealand White rabbits (103 nm), 47 Fauve de Bourgogne rabbits (105 nm), 48 and humans with a healthy liver (107 nm). 49 The diameter in Dutch Belt rabbits was intermediate (124 nm).…”

“…Figure 1C shows the distribution curves for humans, New Zea- land White rabbits, and C57BL/6 mice. These plots were generated by extrapolating the data of frequency distribution histograms 47,49 with a finite number of observations in each individual to curves corresponding to an infinite number of observations. The distribution curves in Figure 1C show a nearly perfect overlap for humans and New Zealand White rabbits, whereas the distribution in C57BL/6 mice is significantly different compared with humans.…”

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

“…Several studies suggest that the size of the endothelial fenestrations of the liver (p100 nm) plays a key role in the efficiency of Ad-mediated hepatocyte transduction (Ad virion X100 nm). 36,37 Specifically, there is a positive correlation between the size of the fenestrations and the efficiency of hepatic transduction following systemic administration HDAd-mediated gene therapy N Brunetti-Pierri and P Ng of Ad. 36 One approach to increase hepatic transduction efficiency may be to use drugs which enlarge liver fenestrations.…”

“…36 One approach to increase hepatic transduction efficiency may be to use drugs which enlarge liver fenestrations. Indeed, Na-decanoate 36 or N-acetylcysteine combined with transient liver ischemia 37 have been shown to increase the size of the sinusoidal fenestrae and increase Ad-mediated hepatocyte transduction. However, further studies are needed to determine the real clinical potential of these pharmacological approaches for human applications.…”

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

“…Upon reaching the liver, the vehicle must then exit the intravascular space to access hepatocytes. Because of the open, fenestrated nature of the hepatic vasculature, particles Ͻ100 nm in diameter can readily exit hepatic vessels and interact with liver parenchymal cells (25). However, avoiding uptake and subsequent activation of Kupffer cells, the resident immune cells of the liver, are likely essential to avoid toxicity (26).…”