Bio-engineered Protein Shows Promise as New Hemophilia Therapy

A genetically engineered clotting factor that controlled hemophilia in an animal study offers a novel potential treatment for human hemophilia and a broad range of other bleeding problems.

Safely controlling bleeding in mice with hemophilia

The researchers took the naturally occurring coagulation factor Xa (FXa), a protein active in blood clotting, and engineered it into a novel variant that safely controlled bleeding in mouse models of hemophilia.

“Our designed variant alters the shape of FXa to make it safer and efficacious compared to the wild-type factor, but much longer-lasting in blood circulation,” said study leader Rodney A. Camire, PhD, a hematology researcher at The Children’s Hospital of Philadelphia and associate professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

“The shape of the variant FXa changes when it interacts with another clotting factor made available following an injury,” added Camire. “This increases the functioning of the protein which helps stop bleeding.”

The study was published in the November 2011 issue of Nature Biotechnology.

Hemophilia causes, effects and treatment

In hemophilia, an inherited single-gene mutation impairs a patient’s ability to produce a blood-clotting protein, leading to spontaneous, sometimes life-threatening bleeding episodes. The two major forms of the disease, which occurs almost solely in males, are hemophilia A and hemophilia B, characterized by which specific clotting factor is deficient.

Patients are treated with frequent infusions of clotting proteins, which are expensive and sometimes stimulate the body to produce antibodies that negate the benefits of treatment.

Roughly 20 to 30 percent of patients with hemophilia A, and 5 percent of patients with hemophilia B develop these inhibiting antibodies. For those patients, the conventional treatment, called “bypass therapy,” is to use drugs such as factor VIIA and activated prothrombin complex concentrates (aPCCs) to restore blood clotting capability. But these agents are costly (as much as $30,000 per treatment) and not always effective.

In the current animal study, Camire said researchers were able to show the variant protein is more effective at a lower dose than FVIIa.

Goal: creating new treatment options

The range of options for hemophilia patients could improve if the study results in animals are duplicated in humans.

“The variant we have developed puts FXa back on the table as a possible therapeutic agent,” Camire said. Naturally occurring (wild-type) FXa, due to its particular shape, is not useful as a therapy because normal biological processes shut down its functioning very quickly.

By custom-designing a different shape for the FXa protein, Camire’s study team gives it a longer period of activity, while also limiting its ability to engage in unwanted biochemical reactions, such as triggering excessive clotting.

“This potentially could lead to a new class of bypass therapy for hemophilia, but acting further downstream in the clot-forming pathway than existing treatments,” said Camire, who has investigated the biochemistry of blood-clotting proteins for more than a decade.

When the FXa variant was infused into mice with hemophilia, it reduced blood loss after injury, and safely restored the animal’s blood clotting ability. Further studies are necessary in large animal models to determine whether this approach can become a clinical treatment for hemophilia patients who have developed inhibitors, or even more broadly as a drug for uncontrolled bleeding in other clinical situations.

About the study 

Funding support for this research came from the National Institutes of Health, Pfizer Inc., and the National Hemophilia Foundation. The first author of the study was Lacramioara Ivanciu, PhD, of The Children’s Hospital of Philadelphia. Other co-authors with Camire were from CHOP, Pfizer, and the Perelman School of Medicine of the University of Pennsylvania.

Ivanciu L, Toso R, Margaritis P, Pavani G, Kim H, Schlachterman A, Liu JH, Clerin V, Pittman DD, Rose-Miranda R, Shields KM, Erbe DV, Tobin JF, and Arruda VR, Camire RM. A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia. Nature Biotechnology. 2011 Oct 23; 29(11):1028-33. doi: 10.1038/nbt.1995. Read the abstract.