Gene Therapy for Hemophilia: Progress to Date.

Hemophilia is a congenital bleeding disorder that affects nearly half a million individuals worldwide. Joint bleeding and other co-morbidities are a significant source of debilitation for this population. Current therapies are effective but must be given lifelong at regular intervals, are costly, and are available to only about 25% of the hemophilia population living in resource-rich countries. Gene therapy for hemophilia has been in development for three decades and is now entering pivotal-stage clinical trials. While many different technology platforms exist for gene therapy, all current clinical trials for hemophilia employ adeno-associated vector (AAV)-based cell transduction. This small viral particle is capable of packaging modified F8 or F9 transgenes, can be generated robustly from cell lines, and transduces several relatively end-differentiated target tissues such as the liver with high efficiency. While pre-existing neutralizing antibodies to the AAV capsid are recognized to limit current therapy, other challenges have been identified in human studies that were not seen in preclinical studies. Both liver transaminase elevations and immune-mediated loss of transgene expression have been observed in clinical trials. Toll-like receptors, cytotoxic T cells, and other components of the immune response have been implicated in the loss of factor expression, but a full understanding of the immune response awaits clarification. Despite these challenges, many patients enrolled in gene therapy trials have attained long-term expression of factors VIII and IX. This emerging technology now represents a cure for the severe bleeding and joint damage associated with hemophilia.

Life-threatening thrombosis complicating the management of hepatic hemorrhage: anticoagulant treatment in a newborn with hemophilia B.

The authors report the case of a neonate presenting with a distended abdomen and shock from factor IX (F.IX) deficiency and intrahepatic bleeding. After resuscitation and treatment with recombinant F.IX through a central venous line, he developed superior vena cava, upper extremity, and intracerebral venous thrombosis resulting in superior vena cava syndrome and intrathalamic hemorrhage. He was treated with F.IX to achieve near-normal F.IX activity levels and with low-dose unfractionated heparin with clinical improvement. F.IX replacement on a subsequent admission was again complicated by upper venous system thrombosis and improved with low-dose heparin. The case illustrates an unusual presentation of hemophilia, life-threatening thrombotic complications associated with factor replacement, and a strategy for anticoagulant management in the setting of hemophilic bleeding.