Gene therapy for hemophilia B in dogs: finally prevention of bleeding, but concerns about inhibitors remain

High and colleagues (page 2670) report complete prevention of spontaneous bleeding in 3 dogs with hemophilia B that were treated with liver-directed gene therapy with an adenovirus-associated virus (AAV) vector. The utilization of a strong liver-specific promoter was what allowed them to achieve 5% to 12% of normal plasma factor IX with a relatively low dose of AAV. Previous studies in dogs and in human patients have resulted in lower than 5% of normal levels, which was still associated with spontaneous bleeding. These results in dogs are very exciting, as effects in large animals are probably most predictive of success in human patients. A clinical trial of gene therapy in humans with hemophilia B that uses a similar AAV vector and a liver-directed approach has just been initiated. This study raises hopes that these patients may become completely independent of factor except during surgery or with trauma.

Although 3 dogs did well, 1 dog that derived from the Auburn University colony with an early truncation mutation developed high titers of an inhibitory antibody in response to the gene therapy and died of a bleeding episode that did not respond to plasma. This result raises the sobering concern that some gene therapy approaches might result in an antibody response that would leave the patient unable to respond to factor during bleeding episodes. Although the inhibitor formation may have been due to other clinical features in this dog and the incidence was less frequent with the liver-directed approach than with a muscle-directed approach in a previous study, the fact remains that one dog had a catastrophic response to the gene therapy. Studies to further define the risk of inhibitors and ways to prevent them, as pioneered by the High laboratory, will be essential prior to applying these treatments to patients that are at high risk for inhibitor development.