Adeno-associated virus-mediated gene transfer for hemophilia B.

Hemophilia is the bleeding diathesis caused by mutations in the gene encoding factor VIII (hemophilia A) or factor IX (hemophilia B). Currently, the disease is treated by intravenous infusion of the missing purified clotting factor. The goal of gene transfer for treating hemophilia is to achieve sustained expression of factor VIII or factor IX at levels high enough to improve the symptoms of the disease. Hemophilia has proven to be an attractive model for those interested in gene transfer, and multiple gene-transfer strategies are currently being investigated for the hemophilias. The most promising preclinical studies have been with adeno-associated viral vectors (AAV); introduction of AAV vectors expressing factor IX into skeletal muscle or liver in hemophilic dogs has resulted in the long-term expression of factor IX at levels that are adequate to improve disease symptoms. Efforts to translate these findings into the clinical arena have proceeded slowly because of the lack of prior clinical experience with parenteral administration of AAV. In a staged approach, AAV-factor IX (AAV-F.IX) was first administered at doses of up to 1.8 x 10(12) vector genomes/kg (vg/kg) into the skeletal muscles of men with hemophilia B. This trial established the safety of parenteral administration and also showed that general characteristics of AAV transduction were similar in mice, dogs, and humans. In an ongoing trial, AAV-F.IX is being administered into the hepatic circulation of men with severe hemophilia B. The goal of these studies is to identify a safe dose that reliably yields circulating levels of factor IX >2% of normal levels in all subjects. This goal has already been achieved in the hemophilia B dog model; the ongoing study will determine whether a similar result can be achieved in humans with hemophilia B.