- Robin Fraser, Department of Pathology, University of Otago, Christchurch, New Zealand;
- Bruce R Dobbs, Departments of Surgery and Gastroenterology, Canterbury District Health Board, Christchurch, New Zealand
Hepatocytes, the major site of protein synthesis, are targets for manipulating plasma protein levels. Our first demonstration of liver sieving (1975) related to chylomicrons, natural “nanovectors” of dietary cholesterol to hepatocytes.
In 2003 we suggested adenovirus gene-vectors were ‘blocked’ by a less porous liver sieve in a non-responsive haemophiliac dog with cirrhosis.
Recent papers from Boston (2009-10), on lipoid nanoparticle (LNP) vectors transporting small inhibitory RNA (siRNA) to hepatocytes, reignited this speculation.
We considered hurdles to intravenously injected LNP include the capillaries of lung, skin, spleen, bone marrow and bowel before reaching the hepatic microcirculation.
Within the hepatic sinusoids, vectors may be removed by phagocytic Kupffer cells or pinocytotic endothelial caveolae, before negotiating fenestrae, to enter the space of Disse to contact hepatocytes.
Recognition by receptors or fusion with the hepatocyte membrane facilitates entry and silencing of mRNA translation.
We predict vectors are camouflaged by adsorbed serum proteins, apolipoproteins or lipids from the action of capillary or circulating enzymes, as with the artificial fat emulsion IntralipidR.
They must be small (<100nm), to pass the fenestrae while diseases, lifestyles, portal pressures, blood-flow and ageing influence fenestral diameters.
Finally, vector surfaces (natural or artificial) must be recognised by hepatocytes.
Findings from the USA have confirmed that LNP vectors transporting siRNA silence factor VII in mice, while adenovectors of the factor IX genes cure haemophiliac dogs.
We hope our symposia with their decades of study of the hepatic sinusoidal cells have aided the perfection of these exciting new therapies.