Re-administering a viral vector-based gene therapy for hemophilia A was shown to be safe and to achieve long-term improvement in a dog model of the disease — even after neutralizing antibodies were evident following the initial treatment.
The study, “An observational study from long-term AAV re-administration in two hemophilia dogs,” was published in the journal Molecular Therapy: Methods & Clinical Development.
Gene therapies have emerged as one of the most promising approaches to possibly curing hemophilia. Most of the tested strategies take advantage of adeno-associated virus (AAV)-based transport vectors to achieve a targeted and stable production of the clotting factor.
Clinical studies show that these AAV vectors to be safe and effective. However, about 50 percent of patients have been found to have anti-AAV antibodies, which significantly limit their therapeutic activity and use.
“Only patients with hemophilia who have little or no neutralizing antibodies against AAV vectors are eligible to receive AAV gene therapy,” the researchers stated.
AAV-based gene therapies are also known to lose their therapeutic activity throughout time, meaning additional administrations may be necessary for sustained, long-term effects. Given that about 1 in every 2 patients may develop anti-AAV antibodies, however, the ability to safely re-use the same therapy is an open question.
To better understand the long-term impact of AAV gene therapy and its re-administration, a research team at the University of North Carolina at Chapel Hill tested its reuse in two dogs with a canine version of hemophilia A.
The animals had received an initial administration of an AAV8 vector encoding the canine clotting factor VIII (FVIII), given in combination with bortezomib, (brand name, Velcade), a proteasome inhibitor that showed potential to enhance the gene transfer in earlier studies. Before treatment, the animals did not had any neutralizing antibodies, but two weeks post-treatment the presence of these antibodies grew by 128 times. Levels of these antibodies then gradually decreased, becoming undetectable again eight years later.
Additional blood analysis confirmed that the dogs had no detectable neutralizing antibody activity. Interestingly, a roughly three-fold increased ability in the AAV8 vector to produce the clotting factor was seen.
At eight years after the first treatment, the team re-administrated the AAV8-FVIII therapy into the dogs, again in combination with bortezomib. Once more, treatment showed an ability to reduce hemorrhage and prevent bleedings.
A prolonged therapeutic effect was also seen in one dog, with sustained production of the wanted clotting factor. But evidence of such production in the other dog disappeared at day 59.
“These results suggest that re-administration is feasible in these dogs after a long-term follow-up from the first AAV administration,” the researchers wrote.
Additional analysis attributed re-treatment failure in the second dog largely to the activation of an immune response activation. The animal showed increased levels of pro-inflammatory, and lower levels of regulatory, signaling molecules. This process was accompanied by an enhanced immune response against the AVV vector but not to the encoded clotting factor, which was detected 17 days after treatment. Production of anti-FVII antibodies was first seen at day 59.
These results demonstrate — for the first time in a canine model of hemophilia A — that it is possible to re-administer the same AVV-based gene therapy with positive results, the researchers said.
“Given the safety and the efficacy of the current hemophilia clinical trials, the feasibility of an AAV vector re-administration would potentially expand the application to patients who lose therapeutic transgene expression later on,” they added.