The liver is a target for gene therapy of inborn errors of metabolism, of\r\nhemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene\r\ntransfer strategy should deliver the transgene DNA to parenchymal liver cells with\r\naccuracy and precision in the absence of side effects. Liver sinusoids are highly specialized\r\ncapillaries with a particular endothelial lining: the endothelium contains open fenestrae,\r\nwhereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer\r\nvectors to the space of Disse, in which numerous microvilli from parenchymal liver cells\r\nprotrude. The small diameter of fenestrae in humans constitutes an anatomical barrier\r\nfor most gene transfer vectors with the exception of adeno-associated viral (AAV)\r\nvectors. Recent studies have demonstrated the superiority of novel AAV serotypes for\r\nhepatocyte-directed gene transfer applications based on enhanced transduction, reduced\r\nprevalence of neutralizing antibodies, and diminished capsid immune responses. In a\r\nlandmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor\r\nIX expressing vector. Notwithstanding significant progress, clinical experience with these\r\ntechnologies remains very limited and many unanswered questions warrant further study.\r\nTherefore, the field should continue to progress as it has over the past decade, cautiously\r\nand diligently.
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