New Treatment Approach for Hemophilia A

By blocking the activity of the common protein furin, patients with hemophilia A may reap unexpected benefits, according to a study published in JCI Insight.

The findings may lead to the development of future treatment options for individuals suffering from this blood disorder.

“The clotting factors involved in hemophilia A and hemophilia B are very different, and this has important implications in devising new treatments,” said lead researcher Valder R. Arruda, MD, PhD.

Researchers discovered that the enzyme furin, found in most cells, improved blood clotting in hemophilia B. However, in hemophilia A, it had opposite effects in which clotting was impaired.

In patients who suffer from hemophilia A, they have a deficiency of clotting factor VIII (FVIII), while patients with hemophilia B have a deficiency in clotting factor IX (FIX).

Normally, either form of hemophilia is treated with intravenous transfusions of proteins in order to replace the missing clotting factors. These replacement drugs contain amino acids that are able to recognize and interact with furin; however, new research shows that this is not always the case.

“We were surprised to find no evidence that furin was required in factor VIII replacement, as it is in factor IX,” Arruda said.

This finding may cause a shakeup in the research world, as nearly 2 decades of gene therapy has been focused on delivering a gene carrying the code to produce the deficient clotting factor in hemophilia. However, most of the research has been focused on hemophilia B, despite hemophilia A being 5 times as common.

This is because the gene encoding FIX is much smaller than the gene for FVIII, meaning it fits better into a vector, usually a harmless virus, designed to deliver therapeutic genes to a patient.

“In gene therapy, size matters,” Arruda said. “It’s important to reduce the gene package for FVIII to the smallest effective size.”

Arruda also stated deleting the furin-recognition components decreased the size of the gene therapy payload, and also strengthened its benefits for treating hemophilia A. During their investigation, researchers bioengineered a new variant protein called FVIII-∆F, which is able to interact with furin.

Next, they used the variant in gene therapy experiments on animals with severe hemophilia A. Researchers found that in mice, FVIII-∆F increased the FVIII levels, and also improved clotting activity.

The gene therapy experiments were also conducted using a well-established dog colony. Researchers found that in the laboratory dogs with naturally-occurring severe hemophilia A, there was decreased bleeding, even when a lower dosage of the gene therapy was used.

Furthermore, the stronger therapeutic effect did not cause higher levels of unwanted immune reactions, which is a common issue with hemophilia A treatment.

“While much work remains to be done to develop this research into clinical applications, our findings could have a promising translational impact, both for protein replacement and gene therapy,” Arruda said. “Because this variant provides more efficient bleeding control than currently available replacement drugs, while avoiding immune reactions, this could address the unmet needs of hemophilia A patients worldwide. It may also advance gene therapy for this disorder as well.”