Advances in gene therapy for hemophilia: basis, current status, and future perspectives

Hemophilia is a congenital hemorrhagic disease caused by genetic abnormalities in coagulation factor VIII or factor IX. Current conventional therapy to prevent bleeding requires frequent intravenous injections of coagulation factor concentrates from early childhood. Accordingly, gene therapy for hemophilia remains an exciting future prospect for patients and their families, due to its potential to cure the disease through a one-time treatment. After a series of successes in basic research, recent clinical trials have demonstrated clear efficacy of gene therapy for hemophilia using adeno-associated virus (AAV) vectors. Although this is likely to alter the paradigm of hemophilia care in the near future, it will be important to overcome immune responses against AAV. Gene therapy for hemophilia cannot be given to patients with anti-AAV capsid-neutralizing antibodies, and cellular immunity with CD8⁺ T cells should be controlled for sustained expression. Furthermore, long-term therapeutic effects should be closely observed because of the failure of the AAV vector genome to replicate during cell division. This review focuses on the basis of gene therapy, current successes of clinical trials, and the future direction of hemophilia gene therapy.