Blood, 15 April 2002, Vol. 99, No. 8, pp. 2635-2636
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.
Katherine Ponder
Washington University School of Medicine
