Viral Vector-Mediated Gene Therapy for Hemophilia

Hemophilia A and B are hereditary coagulation disorders that result from functional deficiencies of factor VIII (FVIII) or factor IX (FIX), respectively. Current treatment consists of injections with plasma-derived or recombinant clotting factors. Despite the significant clinical benefits of protein replacement therapies, these do not constitute a cure and patients are still at risk of bleeding. Significant progress has been made recently in the development of gene therapy for hemophilia. This has been primarily due to the technical improvements of existing vector systems and the development of new gene delivery methods. Therapeutic and sometimes physiologic levels of FVIII and FIX could be achieved in FVIII- and FIX-deficient mice and hemophilic dogs using different types of viral vectors. In these preclinical studies, long-term correction of the bleeding disorders and in some cases a permanent cure has been realized. However, complications related to the induction of neutralizing antibodies or viral promoter inactivation often precludes stable phenotypic correction. Several gene therapy phase I clinical trials have been initiated in patients suffering from severe hemophilia A or B. The results from the extensive pre-clinical studies and the preliminary clinical data are encouraging. It is likely that successful gene therapy for hemophilia will become a reality at the beginning of this new millennium, serving as the trailblazer for gene therapy of other diseases.