Clinical gene transfer studies for hemophilia A.

The recent advances in gene transfer technology have expedited the development of gene therapy for the treatment of hemophilia A. Three different U.S. Food and Drug Administration-approved phase I clinical trials had been initiated using different gene therapy approaches each with their own advantages and limitations. In the first gene therapy trial for hemophilia A, a non-viral approach was being explored for patients with severe hemophilia A using ex vivo transfected dermal fibroblast expressing B-domain-deleted factor VIII ( BDD-FVIII). There were no serious adverse events and some patients appeared to have experienced fewer bleeding episodes with very low levels of FVIII near baseline. In the second trial, onco-retroviral vectors expressing BDD-FVIII were injected by peripheral intravenous infusion in adult patients suffering from severe hemophilia A. The procedure was safe and in some patients FVIII-transduced cells were detectable in the peripheral blood for more than a year. Although no sustained FVIII expression was detectable, occasional modest changes in FVIII levels were apparent, and in some cases a reduced bleeding frequency occurred compared with historical rates. In another trial, one patient suffering from severe hemophilia A has been treated with a high-capacity (or gutless) adenoviral vector expressing full-length FVIII, which appeared to have resulted in 1% of normal FVIII levels for several months. However, a transient inflammatory response with hematologic and liver abnormalities was observed. In conclusion, although modest improvements in clinical end points have been detected in some patients in these early phase I trials, further improvements in gene delivery technologies are warranted to bring hemophilia A gene therapy one step closer to reality.