Abstract
The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently.
Highlights
associated viral (AAV) are small, nonenveloped, single-stranded DNA viruses and belong to the Dependovirus genus of the Parvoviridae family
We have demonstrated that uptake of vectors by non-parenchymal liver cells inversely correlates with transduction of parenchymal liver cells [14] and is mouse strain-dependent
Using state of the art transmission electron microscopy measurements, we have previously demonstrated that the average diameter of fenestrae is significantly larger in Dutch Belt rabbits (124 nm) [32], in Sprague Dawley rats (150 nm in the pericentral area and 175 nm in the periportal area) [28], and in C57BL/6 mice (141 nm) [33] than in humans with a healthy liver
Summary
The liver is a central organ in metabolism. Inborn errors of metabolism may lead to accumulation of toxic products in hepatocytes and extensive hepatotoxicity, as observed in disorders like 1-antitrypsin deficiency, type I tyrosinemia, or Wilson disease [1]. In other metabolic diseases, such as in Crigler-Najjar syndrome type I, ornithine transcarbamylase deficiency, familial hypercholesterolemia, and hemophilia A and B, manifestations are primarily extrahepatic [1]. The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis [2,3]. The real target for hepatocyte-directed gene transfer strategies are the parenchymal liver cells or hepatocytes stricto sensu. The ideal gene transfer strategy should target these cells with accuracy and precision in the absence of any untoward effects. We will discuss the strategic importance of this point for gene transfer development in the two sections
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