that can develop hemophilia B
Gene therapy that produces a potent clotting factor holds promise for treating hemophilia B, researchers have reported in Blood.
The group administered adeno-associated viral-8 (AAV-8) vectors encoding the clotting factor FIX-Padua to mice and dogs with hemophilia B.
The treatment appeared to be safe and effective, did not prompt the formation of inhibitory antibodies, and even eradicated pre-existing inhibitors in one of the dogs.
“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.
For years, researchers have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. But this approach has been hindered by the body’s immune response against vectors.
Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent. So Dr Arruda and his colleagues decided to test gene therapy that used lower doses of AAV-8 vector to produce FIX-Padua.
Dr Arruda was part of a team that discovered FIX-Padua in a young Italian man with thrombophilia. A mutation in the factor IX gene produced the clotting factor, which was named after the patient’s city of residence.
FIX-Padua is hyperfunctional, clotting blood 8 to 12 times more strongly than wild-type factor IX. Therefore, in the current study, the researchers needed to strike a balance—to relieve severe hemophilia in dogs by using a dose strong enough to allow clotting but not enough to cause thrombosis or stimulate immune reactions.
“Our ultimate goal is to translate this approach to humans by adapting this variant protein found in one patient to benefit other patients with the opposite disease,” Dr Arruda said
He and his colleagues tested the safety of canine FIX-Padua (AAV-cFIX-Padua) in 3 dogs, all with naturally occurring types of hemophilia B.
Two of the dogs had never been exposed to clotting factor and had never developed antibodies. Injections of AAV-cFIX-Padua changed their hemophilia from severe to mild. They had no bleeding episodes for up to 2 years and did not develop inhibitory antibodies or thrombosis.
The third dog, Wiley, already had inhibitory antibodies before receiving AAV-cFIX-Padua. Like his peers, Wiley responded to the treatment, and that response persisted for 3 years. AAV-cFIX-Padua also eradicated his inhibitors, which marks the first time this occurred in an animal model with pre-existing antibodies.
Another set of experiments in mice suggested the gene therapy is safe and effective. Mice that received AAV encoding human FIX-Padua (AAV-hFIX-Padua) did not develop antibodies.
And the researchers found that AAV-hFIX-Padua was comparable to wild-type human FIX with regard to long-term expression and toxicity.
Dr Arruda noted that larger studies are needed in dogs with pre-existing inhibitors to confirm these encouraging early results.
In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B—at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.
