Editorial [Hot Topic: Liver Directed Gene Therapy: A Long Road to Clinical Applications (Guest Editor: Nicolas Ferry)]

In 1992, the group of Jim Wilson in Philadelphia conducted the first gene therapy trial aimed at treating a liver inherited disease [1]. This seminal study involved hypercholesterolemic patients suffering from a complete hepatic deficiency of LDL receptor. It was based on an ex vivo strategy which entailed the harvest of hepatocytes from a surgical biopsy followed by transduction of cultured cells with MoMULV retroviral vectors. The corrected cells were then reintroduced via the portal vein. Although no substantial therapeutic effect was observed, this trial demonstrated the feasibility and safety of liver directed gene therapy. Almost ten years thereafter, another liver directed gene therapy protocol was carried out by the group of Kathy High [2]. In that case, recombinant AAV vectors ferrying the human factor IX cDNA were injected directly in the hepatic artery of hemophilia B patients. A significant increase in serum FIX was recorded in some patients receiving the highest vector dose. However, this increase was only transient and disappeared in the following weeks. It was subsequently demonstrated that an immune response against the viral capsid proteins was responsible for the elimination of corrected cells by the immune system. In the meantime, the field of gene therapy was devastated in 1998 by the death of a young patient following administration of adenoviral vectors to treat ornithine carbamyl transferase deficiency [3]. These historical cases epitomize the progress of knowledge in the field of liver directed gene therapy, which has been gained from preclinical as well as clinical studies during the past twenty years. They also point out to the caveats that deserve further attention to improve the therapeutic efficiency of future clinical applications of gene therapy for liver diseases. The liver is an attractive target for gene therapy applications because it is accessible to both ex vivo and in vivo gene therapy strategies. Although the ex vivo approach used in the LDL receptor deficiency trial was limited initially by the low transduction rate of the hepatocytes as well as the poor efficiency of engraftment of the cells, important progress makes this approach still worth of consideration. The particular anatomy of hepatic vascularization makes the liver also readily accessible to in vivo gene transfer strategies based on delivery of vectors to the blood stream. Bloodborn viral particles may easily cross the fenestrated endothelium lining the sinusoidal plates and enter the space of Disse which separates the hepatocyte sinusoidal membrane from the blood vessels. This simplified description may be actually be more complicated. The size of the fenestrations may differ according to the species. Also, non parenchymal cells are present in the vicinity of the space of Diss (Kupffer cells, endothelial cels etc….). All these cells are also the target of gene transfer vectors and contribute, usually negatively, to the final outcome of gene transfer. Such off target infection may result in deleterious responses, as in the case of adenoviral vectors. Furthermore, when expression of the transgene is specifically restricted to hepatocytes, tolerance to the transgene product may ensue with an as yet not clearly defined role of regulatory T cells. Therefore many efforts are devoted to circumvent infection of non parenchymal liver cells.