Induction of factor VIII tolerance by hemophilia gene transfer to eradicate factor VIII inhibitors

Patients with hemophilia A can develop antifactor antibodies to factor VIII. The incidence is ∼30%, and such patients suffer worse morbidity and mortality. The only proven method to eradicate these inhibitors is via immune tolerance induction therapy, which consists of infusing factor VIII concentrates at regular intervals. This approach is effective ∼65% of the time, leaving at least a third of patients who develop inhibitors with this lifelong problem. Although emicizumab has greatly improved the quality of life of inhibitor patients, eradicating the inhibitor remains an important treatment goal. Animal models have shown the potential for gene therapy to induce tolerance. A recent abstract describing a study in humans demonstrated the potential for successful tolerance induction. This article will describe the rationale for using gene therapy to induce tolerance and provide this author's viewpoint on the importance and possible historic significance of attempting to eradicate inhibitors with this approach.