Gene Therapy Results in Sustained Factor VIII Expression and Reduced Bleeding Episodes in Dogs with Severe Hemophilia A

Two young adult male dogs with severe hemophilia A treated with liver-targeted gene therapy experienced significant improvement in disease phenotype over follow-up periods of 31 months and 24 months, according to investigators at The Children’s Hospital of Philadelphia and the University of Pennsylvania. The dogs received separate injections of two adeno-associated viral (AAV) vectors containing the light and heavy chains of recombinant B domain-deleted (BDD) canine factor VIII (cFVIII). Vector administration was well-tolerated. Liver enzymes remained within reference range for both dogs following gene therapy.

For “Dog 1” and “Dog 2,” circulating levels of AAV-cFVIIIBDD remained stable at 1.6 percent to 2 percent and 1 percent of normal, with no evidence of inhibitors to cFVIII. Both dogs, which were privately owned and returned to their families following gene therapy, experienced a 90 percent reduction in spontaneous bleeding episodes over 55 total months of follow-up (a total of three episodes, compared to 22 episodes documented over a total of 41 months preceding AAV injection). The modest relative increase in FVIII activity following AAV gene therapy was sufficient to prevent most spontaneous bleeding in these two severely hemophilic dogs, consistent with conversion to a moderate disease phenotype.

“This is the first report of gene therapy in privately owned dogs with hemophilia A resulting in a significant improvement in the disease phenotype after a single vector injection, resembling the success of early phase clinical trials for humans with hemophilia B,” the investigators concluded.