Abstract
Two ongoing clinical trials utilize different adeno-associated viral (AAV) vectors for liver-directed factor IX (F.IX) gene transfer with the goal of sustained therapy in patients with severe hemophilia B. Although preclinical studies have documented immune tolerance and long-term expression of F.IX in animals, the single prior clinical trial of this approach achieved only transient therapeutic gene expression and exposed preexisting immunity to the AAV vector as a major obstacle for therapy.1 Although accumulating preclinical data continue to fuel a debate over the potential impact of immune responses on hepatic AAV gene transfer, these data do not allow us to predict whether the human immune system will reject or tolerate therapy. This commentary dissects the relevant human and animal data, some of which are contradictory or allow us to draw only limited conclusions. More clinical trial data are critically needed and should ultimately help us develop better protocols.
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