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.
The investigators 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," says study leader Rodney A. Camire, Ph.D., a hematology researcher at Children's Hospital. The study appears in the November issue of Nature Biotechnology.
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.
The range of options for hemophilia patients could improve if the study results in animals were to be duplicated in humans. "The variant we have developed puts FXa back on the table as a possible therapeutic agent," says Dr. Camire. 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, Dr. Camire's study team gives it a longer period of activity, while 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," says Dr. Camire, who has investigated the biochemistry of blood-clotting proteins for more than a decade.