2003; baxter - Supplements - Haematologica

IV International Workshop on Immune Tolerance in Hemophilia 113Figure 3. Components of the gene therapy protocol thatinfluence the likelihood of inhibitor development.Figure 4. Features of the transgene recipient and vectordelivery protocol that are likely to reduce the risk of inhibitordevelopment.moters that mediate ubiquitous transgeneexpression, high vector doses, the study of animalswith an inherited predisposition forinhibitor development and the use of deliverysystems that incite a significant host immuneresponse (Figure 3). As described above, the useof early generation adenovectors is clearly associatedwith the generation of both innate andadaptive host immune responses and these haveincluded the development of inhibitor antibodiesfollowing the delivery of a factor VIII transgene.However, this phenomenon is not consistentlyobserved, and the delivery of factor VIIItransgenes with early generation adenovectors tothe immunotolerant C57BL/6 strain of hemophilicmice has resulted in long-term factor VIIIexpression without the generation ofinhibitors. 12,13 It is too early to predict whetherthe tendency for inhibitor development will bereduced with helper-dependent adenoviral vectorsbut at least one report has already documentedtheir occurrence in some hemophilicmice treated with one of these vectors. 14Strategies to minimize inhibitordevelopment following adenoviralgene therapy for hemophiliaCurrent pre-clinical evidence suggests thateven with the use of homologous transgenes andthe latest generation of helper-dependent adenoviralvectors, inhibitory antibodies can stilldevelop. To minimize the likelihood of this complication,several approaches can be employed inthe selection of transgene recipients and the conductof the gene delivery protocol (Figure 4).Potential transgene recipients with a knownfamilial (strain) propensity for antibody developmentshould be avoided and, where known,recipients with hemophilic genotypes that areassociated with higher risks for inhibitor developmentshould also be excluded from initial trialsof hemophilia gene therapy. In terms of thegene delivery protocol, use of a transgene promoterto prevent transgene expression in antigenpresenting cells and the use of vector dosesthat optimize the balance between transgeneexpression and host immune activation will bothreduce the likelihood of inhibitor development.With specific reference to adenovector delivery,strategies to eliminate or at least minimize theearly innate immune response to the vector willalso likely reduce the subsequent development ofinhibitors.The future of adenoviral gene therapy forhemophiliaWith the development of the latest generationof helper-dependent adenovectors, the potentialfor using these vectors to deliver clotting factortransgenes has been revisited. While residualquestions remain concerning the innate immunitygenerated by these vectors and the durationof transgene expression, their relative ease of production,high transduction efficiency and opportunitiesfor readministration following serotypeswitching with different helper viruses suggeststhat further evaluation of this vector system iswarranted. Nevertheless, until the issues of theinnate immune response and the inter-individualvariability of immune responsiveness are betterunderstood, the evaluation of these vectors, inthe context of hemophilia gene therapy, shouldprobably be restricted to the pre-clinical setting. 15haematologica vol. 88(supplement n. 12):september 2003