Gene therapy for haemophilia: a long and winding road

Summary.  Background:  Cure, or improvement of disease phenotype, has been a long‐term goal in the treatment of haemophilia. An obvious strategy for achieving this goal is the use of gene therapy. Objectives:  This paper summarises prior and current clinical trials of gene therapy for haemophilia A and B, and briefly describes additional strategies in pre‐clinical development. Results and Conclusions:  Approximately 50 human subjects with severe haemophilia A or B have been enrolled in seven different trials of gene therapy. These have used plasmids, retroviral, adenoviral, and AAV vectors, directed to autologous fibroblasts, skeletal muscle, liver, and other target cell types accessed by intravenous injection of vector. Four separate trials have used AAV vectors, three of these targeting liver. Data from animal models suggest that several different gene replacement strategies may eventually yield long‐term expression of factor at therapeutic levels, and that in situ correction of gene defects in hepatocytes may eventually be a therapeutic option.