Gene Therapy Could Generate Powerful Hemophilia Treatment

Process produces protein with high blood clotting ability.

The use of gene therapy could lead to a powerful new treatment for hemophilia, the results of a recent study found.

Published in the print edition of Blood on March 5, 2015, the study examined the use of gene therapy to generate a mutant human protein that carries abnormally high blood-clotting power.

Researchers were able to successfully treat the bleeding disorder in dogs without activating an unwanted immune response. Additionally, the "turbocharged" clotting protein removed existing antibodies that frequently weaken current conventional hemophilia therapies.

"Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies," study lead Valder R. Arruda, MD, PhD, said in a press release.

Current hemophilia treatments involve ongoing intravenous infusions of blood clotting proteins, which can have lose efficacy as patients develop inhibiting antibodies, the study noted.

Researchers have long been evaluating various strategies for gene therapy that can deliver DNA sequences with genetic code that produces clotting factor.

The potential gene therapy has been limited by the immune response against vectors, which mitigated the initial benefits of gene therapy and were dose-dependent, as increasing vector amounts led to greater immune responses.

As a result, the researchers examined gene therapy with lower dosages of adeno-associated viral-8 vector and AAV-8 vector for a more potent clotting factor through a variant protein called FIX-Padua. FIX-Padua was the first mutation in the factor IX gene to cause thrombosis, while FIX mutations that were previously discovered lead to hemophilia.

FIX-Padua has previously been found to clot blood 8 to 12 times more strongly than normal factor IX.

For the current study, the researchers attempted a balance between relieving severe hemophilia through a dose strong enough to allow clotting, without causing thrombosis or stimulating 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.

The researchers evaluated the safety of FIX-Padua in 3 dogs with naturally occurring types of hemophilia B similar to the condition in humans. Two of the 3 canines were never exposed to clotting factor, and as such never developed antibodies.

The gene therapy reduced hemophilia from severe to mild and there were no bleeding episodes reported for up to 2 years. Furthermore, the animals did not develop inhibiting antibodies and there was no evidence of thrombosis.

The third dog already carried the inhibitory antibodies prior to receiving gene therapy. This dog also experienced safe and effective hemophilia treatment, which persisted over a period of 3 years.

In addition, the treatment eliminated inhibitory antibodies in the third dog, which is the first time this observed in an animal with pre-existing antibodies.

A preclinical study of a mouse model also supported the safety and efficacy of the therapy.

The researchers have established a future clinical trial of FIX-Padua in adult patients with hemophilia B at the University of North Carolina at Chapel Hill, while another potential trial is being discussed at Spark Therapeutics in Philadelphia.