Hemophilia treatment. Gene therapy, factor VIII antibodies and immune tolerance: hopes and concerns.

As trials of hemophilia A gene therapy enter the dinic, a continuing concern is the generation of factor VIII inhibitors to the newly delivered transgene product that might also neutralize future factor VIII replacement therapy. A number of factors relating to both the transgene recipient and to the gene therapy process have now been recognized to influence the likelihood of this treatment complication. The recipient's hemophilic mutation and other, far less clearly defined, immunogenic loci are clearly important components in the estimation of inhibitor risk, and need to be taken into account in selecting the initial gene therapy study populations. With regards to the gene delivery process, the choice of vector, site of delivery and tissue restriction of transgene expression have all been identified as factors that influence the subsequent development of a productive immunologic response to the transgene product. Each of these variables has an important effect on the initial event of antigen presentation and appropriate gene therapy strategies have been characterized that will significantly reduce the efficiency of this critical stage in the immunologic response. Finally, additional recipient characteristics such as pre-existing or induced inflammatory conditions or tissue damage have also been demonstrated to increase the subsequent risk of inhibitor development and therefore represent clinical states that should be avoided in the selection of gene therapy recipients and protocols.