Editors' ChoiceHemophilia B

# A New FIX for Hemophilia B

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Science Translational Medicine  11 Jan 2012:
Vol. 4, Issue 116, pp. 116ec5
DOI: 10.1126/scitranslmed.3003668

Hemophilia B is a disabling and life-threatening disease involving an impaired clotting response and uncontrolled bleeding that results from a defect in the gene encoding clotting factor IX (FIX). Whereas the development of clotting factor concentrates and recombinant FIX has dramatically changed the morbidity and mortality of this disease, treatment requires frequent intravenous infusions and is expensive, costing upward of $50,000 to$80,000 annually per affected individual in the United States. Gene therapy to provide hemophilia B patients with a functional copy of the gene encoding FIX is potentially curative; however, to date this strategy has led to only transient expression of FIX. Now, Nathwani et al. present remarkable results from a combined phase 1 and 2 clinical trial of adenovirus-associated virus vector–mediated gene transfer in hemophilia B patients. They report that their gene-therapy treatment led to sustained increases in FIX production in six patients for up to 5 to 15 months.

How did Nathwani and colleagues succeed where others have failed? First, they modified the structure of the FIX gene expression cassette so that it was packaged as a dimer within a single virion in order to improve expression of the gene. The group carefully selected the viral vector, settling eventually on adeno-associated virus serotype 8 (AAV8). AAV8 has a lower seroprevalence in humans and should therefore be less likely to stimulate a humoral immune response. Second, because AAV8 has a strong tropism for the liver, where clotting factors are normally synthesized, the vector could be administered noninvasively by a simple injection into peripheral blood. A total of six patients were treated with one injection and then followed for a period of 5 to 15 months. At baseline, expression of FIX was <1% of normal values. After gene therapy, the FIX concentration increased to 2 to 11% of normal values. Although these effects appear modest, they were associated with a significant decrease in the need for FIX prophylaxis. Four patients were able to completely discontinue FIX replacement therapy, whereas two patients required less frequent infusions of FIX. Two patients showed a transient increase in liver enzymes, which resolved after a short course of steroids and was not associated with loss of FIX expression.

Larger and longer studies will be required before gene therapy becomes standard of care for hemophilia B. However, the results of the Nathwani et al. study are encouraging and point to an emerging new era in the treatment of this tragic bleeding disorder, an era that offers the hope of a “fix” from a single injection for treating hemophilia B.

A. C. Nathwani et al., Adenovirus-associated virus vector–mediated gene transfer in Hemophilia B. N. Eng. J. Med. 365, 2357–2365 (2011). [PubMed]