Gene therapy for hemophilia

Hemophilia A and B are inherited coagulopathies caused by mutations in the factor VIII (FVIII) and factor IX (FIX) gene, respectively. Although today, both diseases are well or excellently be treatable by intravenous substitution of FVIII and FIX concentrates, considerable efforts are being made to develop gene therapy protocols for hemophilia aimed to improving patients' quality of life and to reducing the costs of substitution therapy. Gene therapy aims to correct gene defects and is based principally on the introduction of the intact FVIII or FIX gene into somatic cells. This procedure requires viral transfer vectors. So far, sufficient and even high gene therapeutically expressed concentrations of FVIII/FIX could only be achieved in animal studies, while clinical protocols for humans had to be preliminarily stopped due to inefficacy and side effects. Nevertheless, based on the success of the animal studies, it can be expected that similarly high expression rates can also be achieved in humans. With view to the fact that in the present situation patients are at high risk of developing thrombotic events, this study presents a doxycycline inducible expression system for human FIX integrated within an adenoviral gene transfer vector. After intravenous injection of modified adenoviral vectors in mice, the efficacy of the regulation was demonstrated by measuring the FIX antigen concentration as well as FIX activity in mouse blood. Additionally, by measuring the D-dimer concentration in mouse blood and correlating these values with the gene therapeutically expressed human FIX concentration, we could demonstrate, for the first time, that high expression levels of human FIX in a gene therapy protocol increased the blood procoagulant activity in animals.