1. ¹Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
2. ²Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
3. ³Department of Pediatrics, Howard Hughes Medical Institute, Philadelphia, PA, USA

Correspondence: Dr K High, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, 3615 Civic Center Boulevard, 302 Abramson Research Center, Philadelphia, PA 19104, USA. E-mail: high@email.chop.edu

Received 3 March 2008; Revised 5 March 2008; Accepted 5 March 2008; Published online 24 April 2008.

Abstract

Adeno-associated viral vector-mediated gene transfer of coagulation factor IX to the skeletal muscle or to liver has resulted in sustained correction of hemophilia B in mice and dogs. The two initial phase I/II AAV clinical trials for hemophilia B, delivering a factor IX cDNA to skeletal muscle or liver, showed no serious adverse events. Although the muscle trial failed to achieve a therapeutic level of factor IX in the circulation, long-term expression of clotting factor was demonstrated on muscle biopsies taken up to 3 years after vector injection. Administration of vector to liver via the hepatic artery identified a therapeutic dose, which agreed closely with the doses predicted by studies in hemophilic dogs. However, expression in human subjects lasted for only a period of weeks, followed by a gradual decline in factor IX levels accompanied by a self-limited, asymptomatic rise and fall in liver enzymes. Immune responses to vector capsid may account for this difference in outcome between humans and other species. Here we review the results from both preclinical and clinical studies of adeno-associated viral vector gene transfer for hemophilia B, and the problems that have been identified and that must be overcome to achieve successful transduction and sustained expression.